Substituted piperidine compounds useful as modulators of chemokine receptor activity

ABSTRACT

The invention provides compounds of formula (I) wherein R 1 , R 2 , R 3 , R 6 , Z, Q, m, n, X 1 , X 2 , X 3 , X 4  and T are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them, and their use in therapy, especially for the treatment of chemokine receptor related diseases and conditions

This application is a 371 of PCT/GB00/3179 filed Aug. 18, 2000, which claims benefit of Sweden 9902987-8 filed Aug. 24, 1999.

The present invention relates to substituted piperidine compounds, processes for their preparations, pharmaceutical compositions containing them and their use in therapy.

Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C) and Cys—Cys (C—C) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.

The C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).

The C—C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins 1α and 1β (MIP-1α and MIP-1β).

Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.

The present invention provides a compound of formula (I):

wherein

-   -   Z is CR⁴R⁵, C(O) or CR⁴R⁵—Z¹;     -   Z¹ is C₁₋₄ alkylene (such as CH₂), C₂₋₄ alkenylene (such as         CH═CH) or C(O)NH;     -   R¹ represents a C₁-C₁₂ alkyl group optionally substituted by one         or more substituents independently selected from cyano,         hydroxyl, C₁-C₄ alkoxy (such as methoxy or ethoxy), C₁-C₆         alkylthio (such as methylthio), C₃₋₇ cycloalkyl (such as         cyclopropyl), C₁-C₆ alkoxycarbonyl (such as methoxycarbonyl) and         phenyl (itself optionally substituted by one or more of halogen,         nitro, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl (such as CF₃),         phenyl(C₁-C₆ alkyl) (such as benzyl), C₁-C₆ alkoxy, C₁-C₆         haloalkoxy, S(O)₂(C₁-C₆ alkyl), C(O)NH₂, carboxy or C₁-C₆         alkoxycarbonyl); or     -   R¹ represents C₂-C₆ alkenyl optionally substituted by phenyl         (itself optionally substituted by one or more of halogen, nitro,         cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl(C₁-C₆ alkyl), C₁-C₆         alkoxy, C₁-C₆ haloalkoxy, S(O)₂(C₁-C₆ alkyl), C(O)NH₂, carboxy         or C₁-C₆ alkoxycarbonyl); or     -   R¹ represents a 3- to 14-membered saturated or unsaturated ring         system which optionally comprises up to two ring carbon atoms         that form carbonyl groups and which optionally further comprises         up to 4 ring heteroatoms independently selected from nitrogen,         oxygen and sulphur, wherein the ring system is optionally         substituted by one or more substituents independently selected         from: halogen, cyano, nitro, oxo, hydroxyl, C₁-C₈ alkyl, C₁-C₆         hydroxyalkyl, C₁-C₆ haloalkyl, C₁₋₆ alkoxy(C₁-C₆ alkyl), C₃-C₇         cycloalkyl(C₁-C₆ alkyl), C₁-C₆ alkylthio(C₁-C₆ alkyl), C₁-C₆         alkylcarbonyloxy(C₁-C₆ alkyl), C₁-C₆ alkylS(O)₂(C₁-C₆ alkyl),         aryl(C₁-C₆ alkyl), heterocyclyl(C₁-C₆ alkyl), arylS(O)₂(C₁-C₆         alkyl), heterocyclylS(O)₂(C₁-C₆ alkyl), aryl(C₁-C₆ alkyl)S(O)₂,         heterocyclyl(C₁-C₆ alkyl)S(O)₂, C₂-C₆ alkenyl, C₁-C₆ alkoxy,         carboxy-substituted C₁-C₆ alkoxy, C₁-C₄ haloalkoxy, C₁-C₆         hydroxyalkoxy, C₁-C₆ alkylcarboxy-substituted C₁-C₆ alkoxy,         aryloxy, heterocyclyloxy, C₁-C₆ alkylthio, C₃-C₇         cycloalkyl(C₁-C₆ alkylthio), C₃-C₆ alkynylthio, C₁-C₆         alkylcarbonylamino, C₁-C₆ haloalkylcarbonylamino, SO₃H, —NR⁷R⁸,         —C(O)NR²³R²⁴, S(O)₂NR¹⁸R¹⁹, S(O)₂R²⁰, R²⁵C(O), carboxyl, C₁-C₆         alkoxycarbonyl, aryl and heterocyclyl;     -   wherein the foregoing aryl and heterocyclyl moieties are         optionally substituted by one or more of halogen, oxo, hydroxy,         nitro, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl(C₁-C₆ alkyl),         C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, S(O)₂(C₁-C₆ alkyl), C(O)NH₂,         carboxy or C₁-C₆ alkoxycarbonyl;     -   m is 0 or 1;     -   Q represents an oxygen or sulphur atom or a group NR⁹, C(O),         C(O)NR⁹, NR⁹C(O) or CH═CH;     -   n is 0, 1, 2, 3, 4, 5 or 6 provided that when n is 0, then m is         0;     -   each R² and R³ independently represents a hydrogen atom or a         C₁-C₄ alkyl group, or (CR²R³)_(n) represents C₃-C₇ cycloalkyl         optionally substituted by C₁-C₄ alkyl;     -   T represents a group NR¹⁰, C(O)NR¹⁰, NR¹¹C(O)NR¹⁰ or         C(O)NR¹⁰NR¹¹;     -   X¹, X², X³ and X⁴ are, independently, CH₂, CHR¹² {wherein each         R¹² is, independently, C₁-C₄ alkyl or C₃-C₇ cycloalkyl(C₁-C₄         alkyl)} or C═O; or, when they are CHR¹², the R¹² groups of X¹         and X³ or X⁴, or, X² and X³ or X⁴ join to form a two or three         atom chain which is CH₂CH₂, CH₂CH₂CH₂, CH₂OCH₂ or CH₂SCH₂;         provided always that at least two of X¹, X², X³ and X⁴ are CH₂;     -   R⁴ and R⁵ each independently represent a hydrogen atom or a         C₁-C₄ alkyl group;     -   R⁶ is aryl or heterocyclyl, both optionally substituted by one         or more of: halogen, cyano, nitro, oxo, hydroxyl, C₁-C₈ alkyl,         C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁₋₆ alkoxy(C₁-C₆ alkyl),         C₃-C₇ cycloalkyl(C₁-C₆ alkyl), C₁-C₆ alkylthio(C₁-C₆ alkyl),         C₁-C₆ alkylcarbonyloxy(C₁-C₆ alkyl), C₁-C₆ alkylS(O)₂(C₁-C₆         alkyl), aryl(C₁-C₆ alkyl), heterocyclyl(C₁-C₆ alkyl),         arylS(O)₂(C₁-C₆ alkyl), heterocyclylS(O)₂(C₁-C₆ alkyl),         aryl(C₁-C₆ alkyl)S(O)₂, heterocyclyl(C₁-C₆ alkyl)S(O)₂, C₂-C₆         alkenyl, C₁-C₆ alkoxy, carboxy-substituted C₁-C₆ alkoxy, C₁-C₆         haloalkoxy, C₁-C₆ hydroxyalkoxy, C₁-C₆ alkylcarboxy-substituted         C₁-C₆ alkoxy, aryloxy, heterocyclyloxy, C₁-C₆ alkylthio, C₃-C₇         cycloalkyl(C₁-C₆ alkylthio), C₃-C₆ alkynylthio, C₁-C₆         alkylcarbonylamino, C₁-C₆ haloalkylcarbonylamino, SO₃H,         —NR¹⁶R¹⁷, —C(O)NR²¹R²², S(O)₂NR¹³R¹⁴, S(O)₂R¹⁵, R²⁶C(O),         carboxyl, C₁-C₆ alkoxycarbonyl, aryl and heterocyclyl; wherein         the foregoing aryl and heterocyclyl moieties are optionally         substituted by one or more of halogen, nitro, cyano, C₁-C₆         alkyl, C₁-C₆ haloalkyl, phenyl(C₁-C₆ alkyl), C₁-C₆ alkoxy, C₁-C₆         haloalkoxy, S(O)₂(C₁-C₆ alkyl), C(O)NH₂, carboxy or C₁-C₆         alkoxycarbonyl;     -   R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²¹, R²²,         R²³ and R²⁴ are, independently hydrogen, C₁-C₆ alkyl, C₁-C₆         haloalkyl, C₁-C₆ hydroxyalkyl, C₃-C₇ cycloalkyl, C₃-C₇         cycloalkyl(C₁-C₄ alkyl) or phenyl(C₁-C₆ alkyl); and,     -   R¹⁵ and R²⁰ are, independently, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl,         C₃-C₆ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl) or C₁-C₆ alkyl         optionally substituted by phenyl;     -   R²⁵ and R²⁶ are, independently, C₁-C₆ alkyl or phenyl         (optionally substituted by one or more of halogen, nitro, cyano,         C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl(C₁-C₆ alkyl), C₁-C₆ alkoxy,         C₁-C₆ haloalkoxy, S(O)₂(C₁-C₆ alkyl), C(O)NH₂, carboxy or C₁-C₆         alkoxycarbonyl);     -   or a pharmaceutically acceptable salt thereof, or solvate         thereof, or a solvate of a salt thereof;     -   provided that when T is C(O)NR¹⁰ and R¹ is optionally         substituted phenyl then n is not 0.

Certain compounds of formula (I) are capable of existing in isomeric forms (for example as tautomers, enantiomers, geometric isomers or diastereomers). The present invention encompasses all such isomers and mixtures thereof in all proportions.

Hydroxyalkyl is, for example, 2-hydroxyeth-1-yl. Haloalkyl is, for example, CF₃. Alkoxy is, for example, methoxy or ethoxy. Alkoxy(C₁-C₆ alkyl) is, for example, methoxymethyl or ethoxyethyl. Cycloalkyl is, for example, cyclopropyl or cyclohexyl. Cycloalkyl(C₁-C₆ alkyl) is, for example, cyclopropylmethyl. Alkylthio is, for example, methylthio or ethylthio. Alkylthio(C₁-C₆ alkyl) is, for example, methylthiomethyl. Alkylcarbonyloxy(C₁-C₆ alkyl) is, for example, CH₃C(O)OCH₂. S(O)₂(alkyl) is, for example, CH₃S(O)₂. AlkylS(O)₂(C₁-C₆ alkyl) is, for example, CH₃S(O)₂CH₂. Aryl(C₁-C₆ alkyl) is, for example, benzyl, 2-phenyleth-1-yl or 1-phenyleth-1-yl. Heterocyclyl(C₁-C₆ alkyl) is, for example, heterocyclylmethyl. ArylS(O)₂(C₁-C₆ alkyl) is, for example, phenylS(O)₂CH₂. HeterocyclylS(O)₂(C₁-C₆ alkyl) is, for example, heterocyclylS(O)₂CH₂. Aryl(C₁-C₆ alkyl)S(O)₂ is, for example, benzylS(O)₂. Heterocyclyl(C₁-C₆ alkyl)S(O)₂ is, for example, heterocyclylCH₂S(O)₂. Alkenyl is, for example, vinyl or allyl. Carboxy-substituted C₁-C₆ alkoxy is, for example, HOC(O)CH₂CH₂O. Haloalkoxy is, for example, OCF₃. Hydroxyalkoxy is, for example, HOCH₂CH₂O. Alkylcarboxy-substituted C₁-C₆ alkoxy is, for example, CH₃OC(O)CH₂CH₂O. Aryloxy is, for example, phenoxy.

Heterocyclyloxy is, for example, pyridinyloxy or pyrimidinyloxy. C₃-C₇ cycloalkyl(C₁-C₆ alkylthio) is, for example, cyclopropylCH₂S. Alkynylthio is, for example, propargylthio. Alkylcarbonylamino is, for example, acylamino. Haloalkylcarbonylamino is, for example, ClCH₂C(O)NH. Alkoxycarbonyl is, for example, CH₃OC(O).

Aryl is a carbocyclic aromatic ring optionally fused to one or more carbocyclic rings. Aryl is, for example, phenyl, naphthyl or indanyl.

Heterocyclyl is an aromatic or non-aromatic ring system preferably comprising up to 6 (preferably up to 4) heteroatoms selected from the group comprising nitrogen, oxygen and sulphur, and preferably comprising one, two or three 5- or 6-membered rings. Heterocyclyl is, for example, furyl, thienyl, pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl (for example 2-pyridinyl, 3-pyridinyl or 4-pyridinyl), pyrimidinyl (for example 2-pyrimidinyl or 4-pyrimidinyl), pyrazinyl, pyridazinyl, indolyl, 2,3-dihydroindolyl, benzo[b]furyl, benz[b]thienyl, 2,3-dihydrobenz[b]thienyl (for example 1-dioxo-2,3-dihydrobenz[b]thienyl), benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 2,3-dihydrobenzthiazolyl (for example 2,3-dihydrobenzthiazol-2-onyl which is also known as 2-oxo-1,3-benzothiazol-3(2H)-yl), 1,2,3-benzothiadiazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzothiadiazolyl, 2,1,3-benzoxadiazolyl, quinoxalinyl, dihydro-1-benzopyryliumyl (for example a coumarinyl or a chromenonyl), 1,3-benzodioxolyl (also known as 1,2-methylenedioxyphenyl), 3,4-dihydro-1H-2,1-benzothiazinyl (for example 2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl), purine (for example 1H-purine or 9H-purine), 1H-pyrazolo[3,4-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, quinolinyl (for example 2-quinolinyl, 3-quinolinyl or 4-quinolinyl), isoquinolinyl, quinazolinyl or dibenzothiophenyl; or a ring as shown below:

The group R¹ may represent an optionally substituted 3- to 14-membered (especially 5- to 10-membered) saturated or unsaturated ring system which optionally comprises one or two ring carbon atoms that form carbonyl groups and which optionally further comprises one, two, three or four ring heteroatoms independently selected from nitrogen, oxygen and sulphur. Examples of R¹ ring systems, which can be monocyclic or polycyclic, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, indanyl, furyl, thienyl, pyrrolyl, 2,5-dihydropyrrolyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyridinyl (for example 2-pyridinyl, 3-pyridinyl or 4-pyridinyl), pyrimidinyl (for example 2-pyrimidinyl or 4-pyrimidinyl), pyrazinyl, pyridazinyl, indolyl, 2,3-dihydroindolyl, benzo[b]furyl, benz[b]thienyl, 2,3-dihydrobenz[b]thienyl (for example 1-dioxo-2,3-dihydrobenz[b]thienyl), benzimidazolyl, benztriazolyl, benzoxazolyl, benzthiazolyl, 2,3-dihydrobenzthiazolyl (for example 2,3-dihydrobenzthiazol-2-onyl which is also known as 2-oxo-1,3-benzothiazol-3(2H)-yl), 1,2,3-benzothiadiazolyl, 1,2,3-benzoxadiazolyl, 2,1,3-benzothiadiazolyl, 2,1,3-benzoxadiazolyl, quinoxalinyl, dihydro-1-benzopyryliumyl (for example a coumarinyl or a chromenonyl), 1,3-benzodioxolyl (also known as 1,2-methylenedioxyphenyl), 3,4-dihydro-1H-2,1-benzothiazinyl (for example 2-dioxo-3,4-dihydro-1H-2,1-benzothiazinyl), purine (for example 1H-purine or 9H-purine), 1H-pyrazolo[3,4-d]pyrimidinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, quinolinyl (for example 2-quinolinyl, 3-quinolinyl or 4-quinolinyl), isoquinolinyl, quinazolinyl or dibenzothiophenyl; or a ring as shown below:

In one aspect the present invention provides a compound of formula (Ia):

wherein

-   -   R¹ represents a C₁-C₁₂ alkyl group optionally substituted by one         or more substituents independently selected from cyano,         hydroxyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio and C₁-C₆         alkoxycarbonyl, or     -   R¹ represents a 3- to 10-membered saturated or unsaturated ring         system which optionally comprises up to two ring carbon atoms         that form carbonyl groups and which optionally further comprises         up to 4 ring heteroatoms independently selected from nitrogen,         oxygen and sulphur, wherein the ring system is optionally         substituted by one or more substituents independently selected         from halogen, cyano, nitro, hydroxyl, carboxyl, C₁-C₆ alkyl,         C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁C₆ alkoxy,         carboxy-substituted C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₁-C₆         alkylthiomethyl, C₁-C₆ alkylcarbonylamino, —NR⁷R⁸, —C(O)NR⁷R⁸,         C₁-C₆ alkylcarbonyloxymethyl, C₁-C₆ alkoxycarbonyl, C₁-C₆         alkoxycarbonylpiperazinyl, furyl, phenyl, pyridinyl, pyrazinyl,         halophenyl, thienyl, thienylmethyl, C₁-C₆ alkylbenzyl and     -   m is 0 or 1;     -   Q represents an oxygen or sulphur atom or a group NR⁹, C(O),         C(O)NR⁹ or NR⁹C(O);     -   n is 0, 1, 2, 3 or 4, provided that when n is 0, then m is 0;     -   each R² and R³ independently represents a hydrogen atom or a         C₁-C₄ alkyl group;     -   T represents a group NR¹⁰, C(O)NR¹⁰ or NR¹¹C(O)NR¹⁰;     -   each X independently represents a group CH₂, CHR¹² or C═O,         provided that at least two groups X simultaneously represent         CH₂;     -   R⁴ and R⁵ each independently represent a hydrogen atom or a         C₁-C₄ alkyl group;     -   R⁶ represents a phenyl group optionally substituted by one or         more substituents independently selected from halogen, amino         (—NH₂), nitro, cyano, sulphonyl (—SO₃H), sulphonamido (—SO₂NH₂),         C₁-C₆ alkyl, C₁-C₆ haloalkoxy and C₁-C₆ alkylsulphonyl;     -   R⁷ and R⁸ each independently represent a hydrogen atom or a         group selected from C₁-C₆ hydroxyalkyl, C₃-C₆ cycloalkyl and         C₁-C₆ alkyl optionally substituted by phenyl; R⁹, R¹⁰ and R¹¹         each independently represent a hydrogen atom, or a C₁-C₄ alkyl         or cyclopropylmethyl group; and     -   each R¹² independently represents a C₁-C₄ alkyl or         cyclopropylmethyl group;     -   or a pharmaceutically acceptable salt or solvate thereof.

In the context of the present specification, unless otherwise indicated an alkyl substituent or an alkyl moiety in a substituent group may be linear or branched. Examples of alkyl groups/moieties containing up to twelve carbon atoms include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl and n-dodecyl groups. A C₁-C₆ hydroxyalkyl group will comprise at least one hydroxyl group (e.g. one, two or three hydroxyl groups) which may be attached to an internal or terminal carbon atom of the alkyl chain. Similarly, a carboxy-substituted C₁-C₆ alkoxy group will comprise at least one carboxyl group (e.g. one, two or three carboxyl groups) which may be attached to an internal or terminal carbon atom of the alkyl chain. A C₁-C₆ haloalkyl or C₁-C₆ haloalkoxy group will comprise at least one halogen atom (e.g. one, two, three or four halogen atoms independently selected from fluorine, chlorine, bromine and iodine) which may be attached to an internal or terminal carbon atom of the alkyl chain. A halophenyl group will comprise from 1 to 5 halogen atoms independently selected from fluorine, chlorine, bromine and iodine. A C₁-C₆ alkylbenzyl group will comprise at least one C₁-C₆ alkyl group (e.g. one, two or three C₁-C₆ alkyl groups) attached to the phenyl ring of the benzyl moiety. If there is more than one C₁-C₆ alkyl group attached to the phenyl ring, the groups may be the same or different. In a C₁-C₆ alkoxycarbonylpiperazinyl substituent group, the piperazinyl moiety is attached through a nitrogen atom to the carbonyl moiety. When T represents C(O)NR⁹, it should be understood that the nitrogen atom is attached directly to the six-membered heterocyclic ring in formula (I).

The group R¹ may represent a C₁-C₁₂, preferably C₁-C₁₀, more preferably C₁-C₆, alkyl group optionally substituted by one or more (e.g. one, two, three or four) substituents independently selected from cyano, hydroxyl, C₁-C₆, preferably C₁-C₄, alkoxy, C₁-C₆, preferably C₁-C₄, alkylthio and C₁-C₆ alkoxycarbonyl, preferably C₁-C₄ alkoxycarbonyl.

The group R¹ may alternatively represent an optionally substituted 3- to 10-membered saturated or unsaturated ring system which optionally comprises one or two ring carbon atoms that form carbonyl groups and which optionally further comprises one, two, three or four ring heteroatoms independently selected from nitrogen, oxygen and sulphur. Examples of ring systems that may be used which can be monocyclic or polycyclic include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, pyrazolyl, furyl, thienyl, imidazolyl, quinolinyl (e.g. 2-quinolinyl, 3-quinolinyl or 4-quinolinyl), pyridinyl (e.g. 2-pyridinyl, 3-pyridinyl or 4-pyridinyl), 1,3-benzodioxolyl, thiazolyl, benzimidazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl), triazolyl (such as 1,2,3-triazolyl or 1,2,4-triazolyl), benzothiazolyl, pyrimidinyl (e.g. 2-pyrimidinyl or 4-pyrimidinyl), benzothienyl,

In a further aspect of the invention the ring system of R¹ may be optionally substituted by one or more (e.g. one, two, three or four) substituents independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine); cyano; nitro; hydroxyl; carboxyl; C₁-C₆, preferably C₁-C₄, alkyl (especially methyl or ethyl); C₁-C₆, preferably C₁-C₄, hydroxyalkyl; C₁-C₆, preferably C₁-C₄, haloalkyl (e.g. trifluoromethyl); C₁-C₆, preferably C₁-C₄, alkoxy (especially methoxy, ethoxy, n-propoxy or isopropoxy); carboxy-substituted C₁-C₆, preferably C₁-C₄, alkoxy; C₁-C₆, preferably C₁-C₄, alkylthio (especially methylthio, ethylthio, n-propylthio and tert-butylthio); C₁-C₆, preferably C₁-C₄, alkylthiomethyl (particularly methylthiomethyl); C₁-C₆, preferably C₁-C₄, alkylcarbonylamino (especially methylcarbonylamino); —NR⁷R⁸; —C(O)NR⁷R⁸; C₁-C₆, preferably C₁-C₄, alkylcarbonyloxymethyl (particularly methylcarbonyloxymethyl); C₁-C₆, preferably C₁-C₄, alkoxycarbonyl (especially methoxycarbonyl or ethoxycarbonyl); C₁-C₆, preferably C₁-C₄, alkoxycarbonylpiperazinyl; furyl; phenyl; pyridinyl; pyrazinyl; halophenyl (especially chlorophenyl); thienyl; thienylmethyl; C₁-C₆, preferably C₁-C₄, alkylbenzyl (particularly methylbenzyl); and

In a further aspect R¹ is an aromatic 5-membered heterocyclyl having 2, 3 or 4 ring nitrogen atoms (for example 1,2,4-triazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole or tetrazole) substituted by one heteroaromatic ring (such as pyridine or pyrazole) which is itself optionally substituted by halogen or C₁-C₄ alkyl; or R¹ is halophenyl (for example phenyl optionally substituted (such as in the 4-position) by fluoro or chloro; such as 4-chlorophenyl or 4-fluorophenyl).

In a further aspect of the invention Q is oxygen or m is 0. In another aspect of the invention Q represents a sulphur atom or a group NH, C(O) or NHC(O).

In yet another aspect of the invention n is 1 or 2.

In a further aspect of the invention T represents a group NH, C(O)NH or NHC(O)NH. In another aspect of the invention T represents a NH or C(O)NH group. In a further aspect T is C(O)NH.

In one aspect X¹, X², X³ and X⁴ are all CH₂ or CHR¹², wherein the R¹² groups of X¹ and X³ or X⁴, or, X² and X³ or X⁴ join to form CH₂CH₂; provided always that at least two of X¹, X², X³ and X⁴ are CH₂. In a still further aspect X¹, X², X³ and X⁴ are all CH₂. Preferably, all four groups X represent CH₂.

It is preferred that each R² and R³ independently represents a hydrogen atom or a methyl group, especially a hydrogen atom.

In one aspect R⁴ and R⁵ are hydrogen or C₁-C₄ alkyl. In another aspect R⁴ and R⁵ preferably each represent a hydrogen atom.

In another aspect of the invention R⁶ represents a phenyl group optionally substituted by one or more (e.g. one, two, three or four) substituents independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), amino, nitro, cyano, sulphonyl, sulphonamido, C₁-C₆, preferably C₁-C₄, alkyl, C₁-C₆, preferably C₁-C₄, haloalkoxy, methylenedioxy and C₁-C₆, preferably C₁-C₄, alkylsulphonyl.

In another aspect of the invention R⁶ represents a phenyl group optionally substituted by one or more (e.g. one, two, three or four) substituents independently selected from halogen (e.g. fluorine, chlorine, bromine or iodine), amino, nitro, cyano, sulphonyl, sulphonamido, C₁-C₆, preferably C₁-C₄, alkyl, C₁-C₆, preferably C₁-C₄, haloalkoxy and C₁-C₆, preferably C₁-C₄, alkylsulphonyl.

In a further aspect R⁶ is phenyl optionally substituted by halogen or methylenedioxy. In a still further aspect R⁶ is most preferably a phenyl group substituted by halogen. Examples of R⁶ include 3-chlorophenyl, 4-chlorophenyl or, especially, 3,4-dichlorophenyl.

R⁷ and R⁸ each independently represent a hydrogen atom or a group selected from C₁-C₆, preferably C₁-C₄, hydroxyalkyl, C₃-C₆ cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) and C₁-C₆, preferably C₁-C₄, alkyl optionally substituted by phenyl (e.g. one or two phenyl groups).

Most preferably, R⁷ and R⁸ each independently represent a hydrogen atom, or a group selected from C₂ hydroxyalkyl, cyclopropyl and C₁-C₂ alkyl optionally substituted by phenyl.

Compounds of the invention include all the Examples below, some of which are:

-   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(4-methylbenzyl)amine, -   N-[4-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)phenyl]acetamide, -   3-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)phenol, -   N-[(4-Chloro-1-methyl-1H-pyrazol-3-yl)methyl]-1-(3,4-dichlorobenzyl)-4-piperidinamine, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-[(5-methyl-2-furyl)methyl]amine, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(4-nitrobenzyl)amine, -   N-Benzyl-1-(3,4-dichlorobenzyl)-4-piperidinamine, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(4-fluorobenzyl)amine, -   N-(2,6-Dichlorobenzyl)-1-(3,4-dichlorobenzyl)-4-piperidinamine, -   N,1-Bis(3,4-dichlorobenzyl)-4-piperidinamine, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(2-pyridinylmethyl)amine, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-[(3-methyl-2-thienyl)methyl]amine, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-[(5-methyl-2-thienyl)methyl]amine, -   5-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)-2-methoxyphenol, -   4-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)-2-nitrophenol, -   3-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)-4H-chromen-4-one, -   N-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl]-1-(3,4-dichlorobenzyl)-4-piperidinamine, -   N-[(4-Chloro-1H-pyrazol-3-yl)methyl]-1-(3,4-dichlorobenzyl)-4-piperidinamine, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-{[1-(4-methylbenzyl)-1H-pyrazol-5-yl]methyl}amine, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-[(2-phenyl-1H-imidazol-4-yl)methyl]amine, -   N-[(2-Chloro-3-quinolinyl)methyl]-1-(3,4-dichlorobenzyl)-4-piperidinamine, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-[(6-methyl-2-pyridinyl)methyl]amine, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(3-quinolinylmethyl)amine, -   [5-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)-2-furyl]methyl     acetate, -   4-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(4-pyridinylmethyl)amine, -   5-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)-2-nitrophenol, -   N-[2-(tert-Butylsulfanyl)benzyl]-1-(3,4-dichlorobenzyl)-4-piperidinamine, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(4-ethylbenzyl)amine, -   5-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)-2-hydroxybenzoic     acid, -   N-(1,3-Benzodioxol-4-ylmethyl)-1-(3,4-dichlorobenzyl)-4-piperidinamine, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(1,3-thiazol-2-ylmethyl)amine, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-[(5-ethyl-2-furyl)methyl]amine, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(2-quinolinylmethyl)amine, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(4-quinolinylmethyl)amine, -   5-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)-2-hydroxy-3-methoxybenzoic     acid, -   N-[(4-Bromo-1H-pyrazol-3-yl)methyl]-1-(3,4-dichlorobenzyl)-4-piperidinamine, -   2-[2-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)-6-methoxyphenoxy]acetic     acid, -   N-[(4-Bromo-1-methyl-1H-pyrazol-3-yl)methyl]-1-(3,4-dichlorobenzyl)-4-piperidinamine, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(4-iodobenzyl)amine, -   3-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)-6,7-dimethyl-4H-chromen-4-one, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(4-isopropoxybenzyl)amine, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-[(1-methyl-1H-benzimidazol-2-yl)methyl]amine, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(3-methylbenzyl)amine, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(3-pyridinylmethyl)amine, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(2,4-dimethylbenzyl)amine, -   Ethyl     5-({[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}methyl)-2-methyl-3-furoate, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-3-furamide, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-4-[3-(4-pyridinyl)-1,2,4-oxadiazol-5-yl]butanamide, -   2-{[5-(1-Benzyl-2-oxo-1,2-dihydro-3-pyridinyl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]propanamide, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-6-methoxy-4-quinolinecarboxamide, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-(2-furyl)-4-quinolinecarboxamide, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-4-(2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)butanamide, -   3-(1,3-Benzothiazol-2-ylsulfanyl)-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]propanamide, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-(3,5-dimethoxyphenyl)acetamide, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-(2-methoxyphenyl)acetamide, -   2-[5-Chloro-2-oxo-1,3-benzothiazol-3(2H)-yl]-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]acetamide, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-[(4,6-dimethyl-2-pyrimidinyl)sulfanyl]acetamide, -   2-(1-Benzothiophen-3-yl)-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]acetamide, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-4-(3,4-dimethoxyphenyl)butanamide, -   5-Cyclohexyl-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]pentanamide, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-3-fluoro-2-methylbenzamide, -   N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-(1-phenylethyl)phthalamide, -   2-Cyclopentyl-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]acetamide, -   4-Chloro-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-nitrobenzamide, -   2,2-Dichloro-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-1-methylcyclopropanecarboxamide, -   tert-Butyl     4-[5-({[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}carbonyl)-2-methoxyphenyl]-1-piperazinecarboxylate, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-5-oxo-1-(2-thienylmethyl)-3-pyrrolidinecarboxamide, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-3-[2-oxo-1,3-benzoxazol-3(2H)-yl]propanamide, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-4-fluorobenzamide, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-methylbenzamide, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-3-methylbenzamide, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-4-(hydroxymethyl)benzamide, -   N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-{2-[(methylsulfanyl)methyl]-4-pyrimidinyl}-1,2-ethanediamine, -   N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-[2-(methylsulfanyl)-6-(trifluoromethyl)-4-pyrimidinyl]-1,2-ethanediamine, -   N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-[5-methoxy-2-(methylsulfanyl)-4-pyrimidinyl]-1,2-ethanediamine, -   2-({4-[(2-{[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}ethyl)amino]-2-pyrimidinyl}amino)-1-ethanol, -   N⁴-(2-{[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}ethyl)-6-methyl-2,4-pyrimidinediamine, -   N⁴-(2-{[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}ethyl)-N²,6-dimethyl-2,4-pyrimidinediamine, -   2-Chloro-N⁴-cyclopropyl-N⁶-(2-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}ethyl)-4,6-pyrimidinediamine, -   N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-(4-phenyl-2-pyrimidinyl)-1,2-ethanediamine, -   N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-[4-(trifluoromethyl)-2-pyrimidinyl]-1,2-ethanediamine, -   N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-[4-(propylsulfanyl)-2-pyrimidinyl]-1,2-ethanediamine, -   N²-(2-{[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}ethyl)-N⁴,6-dimethyl-2,4-pyrimidinediamine, -   N⁴-Cyclopropyl-N²-(2-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}ethyl)-2,4-pyrimidinediamine, -   N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-[4-(3-pyridinyl)-2-pyrimidinyl]-1,2-ethanediamine, -   N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-[4-(2-thienyl)-2-pyrimidinyl]-1,2-ethanediamine, -   N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-[4-(2-thienyl)-2-pyrimidinyl]-1,2-ethanediamine, -   N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4yl)-1,2-ethanediamine, -   N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-(1H-purin-6-yl)-1,2-ethanediamine, -   N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-(5-methylthieno[2,3-d]pyrimidin-4-yl)-1,2-ethanediamine, -   N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-(7-methylthieno[3,2-d]pyrimidin-4-yl)-1,2-ethanediamine, -   N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-(9-methyl-9H-purin-6-yl)-1,2-ethanediamine, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-{[5-(trifluoromethyl)-2-pyridinyl]sulfanyl}acetamide, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)acetamide, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-5-oxo-5-phenylpentanamide, -   2-[2-(4-Chlorophenyl)-5-methyl-1,3-thiazol-4-yl]-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]acetamide, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-(phenylsulfanyl)acetamide, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-(4-fluorophenyl)acetamide, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-[2-(2-pyrazinyl)-1,3-thiazol-4-yl]acetamide, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-[(5-phenyl-2-pyrimidinyl)sulfanyl]acetamide, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-3-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanamide, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-1H-benzimidazol-2-amine, -   2-{[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}-N-(3-methoxyphenyl)acetamide,     dihydrochloride salt, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N′-(3,4-dichlorophenyl)urea, -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N′-(3-methoxyphenyl)urea,     and -   N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(4-methoxybenzyl)amine,     dihydrochloride salt.

The present invention further provides a process for the preparation of a compound of formula (I) or (Ia) which comprises:

-   -   (a) when n is at least 1, the CR²R³ group attached directly to T         is CHR³ and T is NR¹⁰, reacting a compound of formula     -    wherein n′ is 0 or an integer from 1 to 3 and R¹, R², R³, m and         Q are as defined above, with a compound of formula     -    or a salt thereof, wherein X¹, X², X³, X⁴, Z, R⁶ and R¹⁰ are as         defined above, in the presence of a reducing agent; or     -   (b) when n is at least 1, the CR²R³ group attached directly to T         is C(C₁-C₄ alkyl)₂ and T is NR¹⁰, reacting a compound of formula     -    wherein n′ is 0 or an integer from 1 to 3, R^(2′) and R^(3′)         each independently represent a C₁-C₄ alkyl group, and R¹, R²,         R³, R¹⁰, m and Q are as defined above, with a compound of         formula     -    wherein X¹, X², X³, X⁴, Z and R⁶ are as defined above, in the         presence of a reducing agent; or     -   (c) when T is C(O)NR¹⁰, reacting a compound of formula     -    wherein R¹, R², R³, Q, m and n are as defined above, with a         compound of formula (III) or a salt thereof as defined in (a)         above; or     -   (d) when m is 1 and Q is NR⁹, reacting a compound of formula         (VII), R¹—L¹, wherein L¹ represents a leaving group (e.g. a         halogen atom) and R¹ is as defined above, with a compound of         formula     -    or a salt thereof, wherein n, T, X¹, X², X³, X⁴, Z, R², R³, R⁶         and R⁹ are as defined above; or     -   (e) when at least one of R⁴ and R⁵ represents a hydrogen atom,         reacting a compound of formula     -    or a salt thereof, wherein R¹, R², R³, Q, m, n, X¹, X², X³, X⁴         and T are as defined above, with a compound of general formula         (X), R⁶—C(O)—R²⁰, wherein R²⁰ represents a hydrogen atom or a         C₁-C₄ alkyl group and R⁶ is as defined above, in the presence of         a reducing agent; or     -   (f) reacting a compound of formula (IX) as defined in (e) above,         with a compound of formula     -    wherein L² represents a leaving group (e.g. a halogen atom) and         Z and R⁶ are as defined above; or     -   (g) when T is NR¹⁰, reacting a compound of formula         R¹—(Q)_(m)—(CR²R³)_(n)—L³  (XII)     -    wherein L³ represents a leaving group (e.g. a halogen atom) and         R¹, R², R³, m, n and Q are as defined above, with a compound of         formula (III) or a salt thereof as defined in (a) above; or     -   (h) when T is NHC(O)NR¹⁰, reacting a compound of formula         R¹—(Q)_(m)—(CR²R³)_(n)—N═C═O  (XIII)     -    wherein R¹, R², R³, Q, m and n are as defined above, with a         compound of formula (III) or a salt thereof as defined in (a)         above; or     -   (i) when T is C(O)NH, Z is CH₂, n is 1, R² and R³ are hydrogen         or C₁-C₄ alkyl and Q is oxygen or sulphur, reacting a compound         of formula (XIV):     -    wherein Hal is a suitable halogen (such as bromo or chloro),         R², R³, X¹, X², X³, X⁴, Z and R⁶ are as defined above, with R¹OH         or R¹SH in the presence of a suitable base (such as potassium         carbonate or sodium or potassium hydroxide);         and optionally after (a), (b), (c), (d), (e), (f), (g), (h)         or (i) forming a pharmaceutically acceptable salt or solvate of         the compound of formula (I) or (Ia)obtained.

Compounds of formulae (II) to (XIV) are either commercially available, or are known in the literature or may be prepared using known techniques.

It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) or (Ia) may involve, at an appropriate stage, the addition and subsequent removal of one or more protecting groups.

The protection and deprotection of functional groups is described in ‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie, Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 2nd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).

The compounds of the invention and intermediates may be isolated from their reaction mixtures, and if necessary further purified, by using standard techniques.

The compounds of formula (I) and (Ia) have activity as pharmaceuticals, in particular as modulators of chemokine receptor activity. More particularly, the compounds have utility as modulators of the activity of chemokine receptors CCR1 and/or CCR3.

A further aspect of the invention involves the use of a compound of formula (I) or (Ia) in the treatment of conditions or diseases in which modulation of chemokine receptor activity is beneficial.

Thus, compounds of formula (I) or (Ia) may be used in the treatment of autoimmune, inflammatory, proliferative and hyperproliferative diseases and immunologically-mediated diseases including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS). Examples of these conditions include:

(1) (the respiratory tract) obstructive airways diseases including chronic obstructive pulmonary disease (COPD); asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyperresponsiveness); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer's lung and related diseases, fibroid lung and idiopathic interstitial pneumonia;

(2) (bone and joints) rheumatoid arthritis, osteoarthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter's disease), Behcet's disease, Sjogren's syndrome and systemic sclerosis;

(3) (skin) psoriasis, atopical dermatitis, contact dermatitis and other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia areata and vernal conjunctivitis;

(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, ulcerative colitis, food-related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema;

(5) (other tissues and systemic disease) multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia pupura; and

(6) (allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease.

Thus, the present invention provides a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a salt thereof, as hereinbefore defined for use in therapy.

In a further aspect, the present invention provides the use of a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a salt thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.

In the context of the present specification, the term “therapy” also includes “prophylaxis” unless there are specific indications to the contrary. The terms “therapeutic” and “therapeutically” should be construed accordingly.

Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disease or condition in question. Persons at risk of developing a particular disease or condition generally include those having a family history of the disease or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disease or condition.

In another aspect the present invention provides the use of a compound of formula (I), wherein Z is CR⁴R⁵, C(O) or CR⁴R⁵—Z¹; Z¹ is C₁₋₄ alkylene, C₂₋₄ alkenylene or C(O)NH: R¹ represents a C₁-C₁₂ alkyl group optionally substituted by one or more substituents independently selected from cyano, hydroxyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio, C₃₋₇ cycloalkyl, C₁-C₆ alkoxycarbonyl and phenyl (itself optionally substituted by one or more of halogen, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl(C₁-C₆ alkyl), C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, S(O)₂(C₁-C₆ alkyl), C(O)NH₂, carboxy or C₁-C₆ alkoxycarbonyl); or R¹ represents C₂-C₆ alkenyl optionally substituted by phenyl (itself optionally substituted by one or more of halogen, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl(C₁-C₆ alkyl), C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, S(O)₂(C₁-C₆ alkyl), C(O)NH₂, carboxy or C₁-C₆ alkoxycarbonyl); or R¹ represents a 3- to 14-membered saturated or unsaturated ring system which optionally comprises up to two ring carbon atoms that form carbonyl groups and which optionally further comprises up to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulphur, wherein the ring system is optionally substituted by one or more substituents independently selected from: halogen, cyano, nitro, oxo, hydroxy, C₁-C₈ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁₋₆ alkoxy(C₁-C₆ alkyl), C₃-C₇ cycloalkyl(C₁-C₆ alkyl), C₁-C₆ alkylthio(C₁-C₆ alkyl), C₁-C₆ alkylcarbonyloxy(C₁-C₆ alkyl), C₁-C₆ alkylS(O)₂(C₁-C₆ alkyl), aryl(C₁-C₆ alkyl), heterocyclyl(C₁-C₆ alkyl), arylS(O)₂(C₁-C₆ alkyl), heterocyclylS(O)₂(C₁-C₆ alkyl), aryl(C₁-C₆ alkyl)S(O)₂, heterocyclyl(C₁-C₆ alkyl)S(O)₂, C₂-C₆ alkenyl, C₁-C₆ alkoxy, carboxy-substituted C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ hydroxyalkoxy, C₁-C₆ alkylcarboxy-substituted C₁-C₆ alkoxy, aryloxy, heterocyclyloxy, C₁-C₆ alkylthio, C₃-C₇ cycloalkyl(C₁-C₆ alkylthio), C₃-C₆ alkynylthio, C₁-C₆ alkylcarbonylamino, C₁-C₆ haloalkylcarbonylamino, SO₃H, —NR⁷R⁸, —C(O)NR²³R²⁴, S(O)₂NR¹⁸R¹⁹, S(O)₂R²⁰, R²⁵C(O), carboxyl, C₁-C₆ alkoxycarbonyl, aryl and heterocyclyl; wherein the foregoing aryl and heterocyclyl moieties are optionally substituted by one or more of halogen, oxo, hydroxy, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl(C₁-C₆ alkyl), C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, S(O)₂(C₁-C₆ alkyl), C(O)NH₂, carboxy or C₁-C₆ alkoxycarbonyl; m is 0 or 1; Q represents an oxygen or sulphur atom or a group NR⁹, C(O), C(O)NR⁹, NR⁹C(O) or CH═CH; n is 0, 1, 2, 3, 4, 5 or 6 provided that when n is 0, then m is 0; each R² and R³ independently represents a hydrogen atom or a C₁-C₄ alkyl group, or (CR²R³)_(n) represents C₃-C₇ cycloalkyl optionally substituted by C₁-C₄ alkyl; T represents a group NR¹⁰, C(O)NR¹⁰, NR¹¹C(O)NR¹⁰ or C(O)NR¹⁰NR¹¹; X¹, X², X³ and X⁴ are, independently, CH₂, CHR¹² {wherein each R¹² is, independently, C₁-C₄ alkyl or C₃-C₇ cycloalkyl(C₁-C₄ alkyl)} or C═O; or, when they are CHR¹², the R¹² groups of X¹ and X³ or X⁴, or, X² and X³ or X⁴ join to form a two or three atom chain which is CH₂CH₂, CH₂CH₂CH₂, CH₂OCH₂ or CH₂SCH₂; provided always that at least two of X¹, X², X³ and X⁴ are CH₂; R⁴ and R⁵ each independently represent a hydrogen atom or a C₁-C₄ alkyl group; R⁶ is aryl or heterocyclyl, both optionally substituted by one or more of: halogen, cyano, nitro, oxo, hydroxyl, C₁-C₈ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁₋₆ alkoxy(C₁-C₆ alkyl), C₃-C₇ cycloalkyl(C₁-C₆ alkyl), C₁-C₆ alkylthio(C₁-C₆ alkyl), C₁-C₆ alkylcarbonyloxy(C₁-C₆ alkyl), C₁-C₆ alkylS(O)₂(C₁-C₆ alkyl), aryl(C₁-C₆ alkyl), heterocyclyl(C₁-C₆ alkyl), arylS(O)₂(C₁-C₆ alkyl), heterocyclylS(O)₂(C₁-C₆ alkyl), aryl(C₁-C₆ alkyl)S(O)₂, heterocyclyl(C₁-C₆ alkyl)S(O)₂, C₂-C₆ alkenyl, C₁-C₆ alkoxy, carboxy-substituted C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ hydroxyalkoxy, C₁-C₆ alkylcarboxy-substituted C₁-C₆ alkoxy, aryloxy, heterocyclyloxy, C₁-C₆ alkylthio, C₃-C₇ cycloalkyl(C₁-C₆ alkylthio), C₃-C₆ alkynylthio, C₁-C₆ alkylcarbonylamino, C₁-C₆ haloalkylcarbonylamino, SO₃H, —NR¹⁶R¹⁷, —C(O)NR²¹R²², S(O)₂NR¹³R¹⁴, S(O)₂R¹⁵, R²⁶C(O), carboxyl, C₁-C₆ alkoxycarbonyl, aryl and heterocyclyl; wherein the foregoing aryl and heterocyclyl moieties are optionally substituted by one or more of halogen, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl(C₁-C₆ alkyl), C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, S(O)₂(C₁-C₆ alkyl), C(O)NH₂, carboxy or C₁-C₆ alkoxycarbonyl; R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²¹, R²², R²³ and R²⁴ are, independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl) or phenyl(C₁-C₆ alkyl); R¹⁵ and R²⁰ are, independently, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₃-C₆ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl) or C₁-C₆ alkyl optionally substituted by phenyl; and, R²⁵ and R²⁶ are, independently, C₁-C₆ alkyl or phenyl (optionally substituted by one or more of halogen, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl(C₁-C₆ alkyl), C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, S(O)₂(C₁-C₆ alkyl), C(O)NH₂, carboxy or C₁-C₆ alkoxycarbonyl); or a pharmaceutically acceptable salt thereof, or solvate thereof, or a solvate of a salt thereof; in the manufacture of a medicament for the modulation of a chemokine receptor (such as CCR1 or CCR3). In a further aspect such medicament is for the treatment of asthma.

The invention also provides a method of treating an inflammatory disease in a person suffering from, or at risk of, said disease, which comprises administering to the person a therapeutically effective amount of a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a salt thereof, as hereinbefore defined.

For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.

A compound of formula (I) or (Ia) or a pharmaceutically acceptable salt, solvate or solvate of a salt, may be used on its own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) or (Ia) compound, salt, solvate or solvate of salt (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (percent by weight), more preferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of active ingredient, all percentages by weight being based on total composition.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate or solvate of salt thereof, as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or (Ia), or a pharmaceutically acceptable salt, solvate or solvate of salt thereof, as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or carrier.

The pharmaceutical compositions may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders, aerosols or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally.

The present invention will be further explained by reference to the following illustrative examples.

Examples 1-47 (i) tert-Butyl 1-(3,4-dichlorobenzyl)-4-piperidinylcarbamate

Sodium triacetoxyborohydride (6 g) was added to a stirred solution of 3,4-dichlorobenzaldehyde (4.2 g) and 1,1-dimethylethyl-4-piperidinyl carbamate (4 g) in dichloromethane (50 ml). The mixture was stirred at room temperature for 4 h then partitioned between ethyl acetate and aqueous sodium hydrogencarbonate. The organic layer was washed with water, dried and evaporated under reduced pressure. The residue was triturated with ether to give a white solid (3.5 g). Used directly.

(ii) 1-(3,4-Dichlorobenzyl)-4-piperidinamine, di-trifluoroacetate salt

The product from step (i) (3.5 g) was treated with trifluoroacetic acid (10 ml) in dichloromethane (40 ml). After 72 h, the solution was evaporated, the residue triturated with ether and the solid (4.3 g) collected.

MS: APCI(+ve) 259/61 (M+1)

(iii) Examples 1-47

The product from step (ii) (2 mg), the appropriate aldehyde (2 equivalents), sodium triacetoxyborohydride (3 equivalents) and diisopropylethylamine (2 equivalents) in acetonitrile (0.08 ml) and 1-methyl-2-pyrrolidinone (0.12 ml) was left at room temperature for 24 h. The reaction mixture was evaporated to dryness and the residue dissolved in dimethylsuphoxide (0.4 ml).

Example 1 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(4-methylbenzyl)amine

MS: APCI(+ve) 363 (M+1)

Example 2 N-[4-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)phenyl]acetamide

MS: APCI(+ve) 406 (M+1)

Example 3 3-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)phenol

MS: APCI(+ve) 365 (M+1)

Example 4 N-[(4-Chloro-1-methyl-1H-pyrazol-3-yl)methyl]-1-(3,4-dichlorobenzyl)-4-piperidinamine

MS: APCI(+ve) 389 (M+1)

Example 5 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-[(5-methyl-2-furyl)methyl]amine

MS: APCI(+ve) 353 (M+1)

Example 6 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(4-nitrobenzyl)amine

MS: APCI(+ve) 394 (M+1)

Example 7 N-Benzyl-1-(3,4-dichlorobenzyl)-4-piperidinamine

MS: APCI(+ve) 349 (M+1)

Example 8 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(4-fluorobenzyl)amine

MS: APCI(+ve) 367 (M+1)

Example 9 N-(2,6-Dichlorobenzyl)-1-(3,4-dichlorobenzyl)-4-piperidinamine

MS: APCI(+ve) 419 (M+1)

Example 10 N,1-Bis(3,4-dichlorobenzyl)-4-piperidinamine

MS: APCI(+ve) 419 (M+1)

Example 11 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(2-pyridinylmethyl)amine

MS: APCI(+ve) 350 (M+1)

Example 12 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-[(3-methyl-2-thienyl)methyl]amine

MS: APCI(+ve) 369 (M+1)

Example 13 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-[(5-methyl-2-thienyl)methyl]amine

MS: APCI(+ve) 369 (M+1)

Example 14 5-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)-2-methoxyphenol

MS: APCI(+ve) 395 (M+1)

Example 15 4-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)-2-nitrophenol

MS: APCI(+ve) 410 (M+1)

Example 16 3-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)-4H-chromen-4-one

MS: APCI(+ve) 417 (M+1)

Example 17 N-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)methyl]-1-(3,4-dichlorobenzyl)-4-piperidinamine

MS: APCI(+ve) 403 (M+1)

Example 18 N-[(4-Chloro-1H-pyrazol-3-yl)methyl]-1-(3,4-dichlorobenzyl)-4-piperidinamine

MS: APCI(+ve) 373 (M+1)

Example 19 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-{[1-(4-methylbenzyl)-1H-pyrazol-5-yl]methyl}amine

MS: APCI(+ve) 443 (M+1)

Example 20 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-[(2-phenyl-1H-imidazol-4-yl)methyl]amine

MS: APCI(+ve) 414 (M+1)

Example 21 N-[(2-Chloro-3-quinolinyl)methyl]-1-(3,4-dichlorobenzyl)-4-piperidinamine

MS: APCI(+ve) 434 (M+1)

Example 22 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-[(6-methyl-2-pyridinyl)methyl]amine

MS: APCI(+ve) 364 (M+1)

Example 23 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(3-quinolinylmethyl)amine

MS: APCI(+ve) 400 (M+1)

Example 24 [5-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)-2-furyl]methyl acetate

MS: APCI(+ve) 411 (M+1)

Example 25 4-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)-1,5-dimethyl-2-phenyl-1,2-dihydro-3H-pyrazol-3-one

MS: APCI(+ve) 459 (M+1)

Example 26 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(4-pyridinylmethyl)amine

MS: APCI(+ve) 350 (M+1)

Example 27 5-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)-2-nitrophenol

MS: APCI(+ve) 410 (M+1)

Example 28 N-[2-(tert-Butylsulfanyl)benzyl]-1-(3,4-dichlorobenzyl)-4-piperidinamine

MS: APCI(+ve) 437 (M+1)

Example 29 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(4-ethylbenzyl)amine

MS: APCI(+ve) 377 (M+1)

Example 30 5-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)-2-hydroxybenzoic acid

MS: APCI(+ve) 409 (M+1)

Example 31 N-(1,3-Benzodioxol-4-ylmethyl)-1-(3,4-dichlorobenzyl)-4-piperidinamine

MS: APCI(+ve) 393 (M+1)

Example 32 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(1,3-thiazol-2-ylmethyl)amine

MS: APCI(+ve) 356 (M+1)

Example 33 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-[(5-ethyl-2-furyl)methyl]amine

MS: APCI(+ve) 367 (M+1)

Example 34 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(2-quinolinylmethyl)amine

MS: APCI(+ve) 400 (M+1)

Example 35 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(4-quinolinylmethyl)amine

MS: APCI(+ve) 400 (M+1)

Example 36 5-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)-2-hydroxy-3-methoxybenzoic acid

MS: APCI(+ve) 439 (M+1)

Example 37 N-[(4-Bromo-1H-pyrazol-3-yl)methyl]-1-(3,4-dichlorobenzyl)-4-piperidinamine

MS: APCI(+ve) 419 (M+1)

Example 38 2-[2-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)-6-methoxyphenoxy]acetic acid

MS: APCI(+ve) 453 (M+1)

Example 39 N-[(4-Bromo-1-methyl-1H-pyrazol-3-yl)methyl]-1-(3,4-dichlorobenzyl)-4-piperidinamine

MS: APCI(+ve) 433 (M+1)

Example 40 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(4-iodobenzyl)amine

MS: APCI(+ve) 475 (M+1)

Example 41 3-({[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}methyl)-6,7-dimethyl-4H-chromen-4-one

MS: APCI(+ve) 445 (M+1)

Example 42 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(4-isopropoxybenzyl)amine

MS: APCI(+ve) 407 (M+1)

Example 43 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-[(1-methyl-1H-benzimidazol-2-yl)methyl]amine

MS: APCI(+ve) 403 (M+1)

Example 44 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(3-methylbenzyl)amine

MS: APCI(+ve) 363 (M+1)

Example 45 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(3-pyridinylmethyl)amine

MS: APCI(+ve) 350 (M+1)

Example 46 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(2,4-dimethylbenzyl)amine

MS: APCI(+ve) 377 (M+1)

Example 47 Ethyl 5-({[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}methyl)-2-methyl-3-furoate

MS: APCI(+ve) 425 (M+1)

Examples 48-73 (i) Examples 48-73

Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (2 equiv) was added to a solution of the product from Example 1 step (ii) (hydrochloride salt) (1 mg), the appropriate acid (2 equivalents) and diisopropylethylamine (5 equivalents) in dimethylformamide (0.17 ml) and was left at room temperature for 24 h. The reaction mixture was evaporated to dryness and the residue dissolved in dimethylsulphoxide (0.3 ml).

Example 48 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-3-furamide

MS: APCI(+ve) 353 (M+1)

Example 49 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-4-[3-(4-pyridinyl)-1,2,4-oxadiazol-5-yl]butanamide

MS: APCI(+ve) 474 (M+1)

Example 50 2-{[5-(1-Benzyl-2-oxo-1,2-dihydro-3-pyridinyl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]propanamide

MS: APCI(+ve) 611 (M+1)

Example 51 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-6-methoxy-4-quinolinecarboxamide

MS: APCI(+ve) 444 (M+1)

Example 52 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-(2-furyl)-4-quinolinecarboxamide

MS: APCI(+ve) 480 (M+1)

Example 53 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-4-(2-methyl-1-oxo-1,2-dihydro-3-isoquinolinyl)butanamide

MS: APCI(+ve) 486 (M+1)

Example 54 3-(1,3-Benzothiazol-2-ylsulfanyl)-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]propanamide

MS: APCI(+ve) 480 (M+1)

Example 55 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-(3,5-dimethoxyphenyl)acetamide

MS: APCI(+ve) 437 (M+1)

Example 56 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-(2-methoxyphenyl)acetamide

MS: APCI(+ve) 407 (M+1)

Example 57 2-[5-Chloro-2-oxo-1,3-benzothiazol-3(2H)-yl]-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]acetamide

MS: APCI(+ve) 486 (M+1)

Example 58 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-[(4,6-dimethyl-2-pyrimidinyl)sulfanyl]acetamide

MS: APCI(+ve) 439 (M+1)

Example 59 2-(1-Benzothiophen-3-yl)-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]acetamide

MS: APCI(+ve) 433 (M+1)

Example 60 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-4-(3,4-dimethoxyphenyl)butanamide

MS: APCI(+ve) 465 (M+1)

Example 61 5-Cyclohexyl-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]pentanamide

MS: APCI(+ve) 425 (M+1)

Example 62 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-3-fluoro-2-methylbenzamide

MS: APCI(+ve) 395 (M+1)

Example 63 N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-(1-phenylethyl)phthalamide

MS: APCI(+ve) 510 (M+1)

Example 64 2-Cyclopentyl-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]acetamide

MS: APCI(+ve) 369 (M+1)

Example 65 4-Chloro-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-nitrobenzamide

MS: APCI(+ve) 444 (M+1)

Example 66 2,2-Dichloro-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-1-methylcyclopropanecarboxamide

MS: APCI(+ve) 411 (M+1)

Example 67 tert-Butyl 4-[5-({[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}carbonyl)-2-methoxyphenyl]-1-piperazinecarboxylate

MS: APCI(+ve) 577 (M+1)

Example 68 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-5-oxo-1-(2-thienylmethyl)-3-pyrrolidinecarboxamide

MS: APCI(+ve) 466 (M+1)

Example 69 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-3-[2-oxo-1,3-benzoxazol-3(2H)-yl]propanamide

MS: APCI(+ve) 448 (M+1)

Example 70 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-4-fluorobenzamide

MS: APCI(+ve) 381 (M+1)

Example 71 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-methylbenzamide

MS: APCI(+ve) 377 (M+1)

Example 72 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-3-methylbenazmide

MS: APCI(+ve) 377 (M+1)

Example 73 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-4-(hydroxymethyl)benzamide

MS: APCI(+ve) 393 (M+1)

Examples 74-93 (i) 1-(3,4-Dichlorobenzyl)-4-piperidinone

A solution of 3,4-dichlorobenzyl chloride (2.8 ml), 4-ketopiperidine hydrochloride monohydrate and triethylamine (8 ml) in dimethylformamide (30 ml) was stirred at room temperature for 20 h. The mixture was partitioned between water and ethyl acetate, the organic layer dried and evaporated under reduced pressure. Purification was by chromatography eluting with 40-50% ethyl acetate/isohexane. Yield 2.1 g.

MS: APCI(+ve) 258/60 (M+1)

(ii) tert-Butyl-2-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}ethylcarbamate

A solution of the product from step (i) (1.61 g), N-(tert-butoxycarbonyl)-ethylenediamine (1 g) and sodium triacetoxyborohydride (2.12 g) in dichloromethane (20 ml) was stirred at room temperature for 3 h. The mixture was partitioned between water and ethyl acetate, the organic layer dried and evaporated under reduced pressure. Yield 1.28 g.

MS: APCI(+ve) 402/4 (M+1)

(iii) N-1-[1-(3,4- Dichlorobenzyl)-4-piperidinyl]-1,2-ethanediamine, tri-trifluoroacetate Salt

The product from step (ii) (1.28 g) was treated with trifluoroacetic acid (5 ml) in dichloromethane (10 ml). After 20 h, the solution was evaporated, the residue triturated with ether and the solid (1.62 g) collected.

MS: APCI(+ve) 302/4 (M+1)

(iv) Examples 74-93

The product from step (iii) (0.0026 g), the appropriate activated halo-aromatic (1.25 equivalents) and diisopropylethylamine (10 equivalents) in 1-methyl-2-pyrrolidinone (0.15 ml) was heated at 100° C. for 20 h. The reaction mixture was evaporated to dryness and the residue dissolved in dimethylsuphoxide (0.4 ml).

Example 74 N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-{2-[(methylsulfanyl)methyl]-4-pyrimidinyl}-1,2-ethanediamine

MS: APCI(+ve) 440(M+1)

Example 75 N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-[2-(methylsulfanyl)-6-(trifluoromethyl)-4-pyrimidinyl]-1,2-ethanediamine

MS: APCI(+ve) 494(M+1)

Example 76 N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-[5-methoxy-2-(methylsulfanyl)-4-pyrimidinyl]-1,2-ethanediamine

MS: APCI(+ve) 456(M+1)

Example 77 2-({4-[2-{[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}ethyl)amino]-2-pyrimidinyl}amino)-1-ethanol

MS: APCI(+ve) 439(M+1)

Example 78 N⁴-(2-{[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}ethyl)-6-methyl-2,4-pyrimidinediamine

MS: APCI(+ve) 409(M+1)

Example 79 N⁴-(2-{[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}ethyl)-N²,6-dimethyl-2,4-pyrimidinediamine

MS: APCI(+ve) 423(M+1)

Example 80 2-Chloro-N⁴-cyclopropyl-N⁶-(2-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}ethyl)-4,6-pyrimidinediamine

MS: APCI(+ve) 471(M+1)

Example 81 N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-(4-phenyl-2-pyrimidinyl)-1,2-ethanediamine

MS: APCI(+ve) 456(M+1)

Example 82 N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-[4-(trifluoromethyl)-2-pyrimidinyl]-1,2-ethanediamine

MS: APCI(+ve) 448(M+1)

Example 83 N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-[4-(propylsulfanyl)-2-pyrimidinyl]-1,2-ethanediamine

MS: APCI(+ve) 454(M+1)

Example 84 N²-(2-{[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}ethyl)-N⁴,6-dimethyl-2,4-pyrimidinediamine

MS: APCI(+ve) 423(M+1)

Example 85 N⁴-Cyclopropyl-N²-(2-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}ethyl)-2,4-pyrimidinediamine

MS: APCI(+ve) 435(M+1)

Example 86 N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-[4-(3-pyridinyl)-2-pyrimidinyl]-1,2-ethanediamine

MS: APCI(+ve) 457(M+1)

Example 87 N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-[4-(3-thienyl)-2-pyrimidinyl]-1,2-ethanediamine

MS: APCI(+ve) 462(M+1)

Example 88 N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-[4-(2-thienyl)-2-pyrimidinyl]-1,2-ethanediamine

MS: APCI(+ve) 462(M+1)

Example 89 N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-(1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-1,2-ethanediamine

MS: APCI(+ve) 434(M+1)

Example 90 N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-(1H-purin-6-yl)-1,2-ethanediamine

MS: APCI(+ve) 420(M+1)

Example 91 N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-(5-methylthieno[2,3-d]pyrimidin-4-yl)-1,2-ethanediamine

MS: APCI(+ve) 450(M+1)

Example 92 N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-(7-methylthieno[3,2-d]pyrimidin-4-yl)-1,2-ethanediamine

MS: APCI(+ve) 450(M+1)

Example 93 N¹-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N²-(9-methyl-9H-purin-6-yl)-1,2-ethanediamine

MS: APCI(+ve) 434(M+1)

Example 94 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-{[5-(trifluoromethyl)-2-pyridinyl]sulfanyl}acetamide

Carbonyldiimidazole (0.105 g) was added to a stirred solution of 2-{[5-(trifluoromethyl)-2-pyridinyl]sulfanyl}acetic acid (0.166 g) in dimethylformamide (2 ml). After 1 h a solution of the product from Example 1 step (ii) (0.3 g) in a solution of dimethylformamide and diisopropylethylamine (2 equivalents) (1.5 ml) was added and stirred at room temperature for 2 h. The mixture was partitioned between water and ethyl acetate, the organic layer washed with water, dried and evaporated under reduced pressure. The residue was triturated with ether and collected. Yield 0.084 g as a solid.

MS: APCI(+ve) 478/80 (M+1)

¹H NMR: δ (DMSO-d6) 8.76(s,1H), 8.11(d, 1H), 8.02(dd, 1H), 7.59-7.53(m, 3H), 7.29(dd, 1H), 3.91(s, 1H), 3.58-3.45(m, 1H), 3.44(s, 2H), 2.70(br d, 2H), 2.03(br t, 2H), 1.70(br d, 2H), 1.46-1.37(m, 2H).

MP: 98° C.

Example 95 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)acetamide

The title compound was prepared from the product of Example 1 step (ii) (0.3 g) and of 2-(5-methyl-1-phenyl-1H-pyrazol-4-yl)acetic acid (0.151 g) using the method of Example 94. Yield 0.18 g as a solid.

MS: APCI(+ve) 457/9 (M+1)

¹H NMR: δ (DMSO-d6) 7.90(d, 1H), 7.59-7.38(m, 8H), 7.29(dd, 1H), 3.54-3.50(m, 1H), 3.45(s, 2H), 3.24(s, 2H), 2.72(br d, 2H), 2.24(s, 3H), 2.03(br t, 2H), 1.72(br d, 2H), 1.46-1.37(m, 2H).

MP: 165° C.

Example 96 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-5-oxo-5-phenylpentanamide

The title compound was prepared from the product of Example 1 step (ii) (0.3 g) and of 5-oxo-5-phenylpentanoic acid (0.134 g) using the method of Example 94. Yield 0.149 g as a solid.

MS: APCI(+ve) 433/5 (M+1)

¹H NMR: δ (DMSO-d6) 7.96-7.93(m, 2H), 7.72(d, 1H), 7.65-7.50(m, 5H), 7.28(dd, 1H), 3.57-3.48(m, 1H), 3.44(s, 2H), 3.01(t, 2H), 2.72-2.67(m, 2H), 2.13(t, 2H), 2.04-1.98(m, 2H), 1.86-1.79(m, 2H), 1.69(br s, 2H), 1.41-1.32(m, 2H).

MP: 130° C.

Example 97 2-[2-(4-Chlorophenyl)-5-methyl-1,3-thiazol-4-yl]-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]acetamide

The title compound was prepared from the product of Example 1 step (ii) (0.3 g) and 2-[2-(4-chlorophenyl)-5-methyl-1,3-thiazol-4-yl]acetic acid (0.187 g) using the method of Example 94. Yield 0.1 g as a solid.

MS: APCI(+ve) 510/2 (M+1)

¹H NMR: δ (DMSO-d6) 8.00(d, 1H), 7.85-7.82(m, 2H), 7.59-7.52(m, 4H), 7.29(dd, 1H), 3.57-3.51(m, 3H), 3.44(s, 2H), 2.72(br d, 2H), 2.41(s, 3H), 2.06(t, 2H), 1.73(br d, 2H), 1.48-1.38(m, 2H).

MP: 170° C.

Example 98 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-(phenylsulfonyl)acetamide

The title compound was prepared from the product of Example 1 step (ii) (0.3 g) and 2-(phenylsulfanyl)acetic acid (0.118 g) using the method of Example 94. Yield 0.056 g as a solid.

MS: APCI(+ve) 409(M+1)

¹H NMR: δ (DMSO-d6) 8.00(d, 1H), 7.57(d, 1H), 7.53(d, 1H), 7.36-7.27(m, 5H), 7.20-7.16(m, 1H), 3.61(s, 2H), 3.55-3.47(m, 1H), 3.44(s, 2H), 2.69-2.66(m, 2H), 2.02(t, 2H), 1.67-1.64(m, 2H), 1.41-1.31(m, 2H).

MP: 97-99° C.

Example 99 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-(4-fluorophenyl)acetamide

The title compound was prepared from the product of Example 1 step (ii) (0.3 g) and 2-(4-fluorophenyl)acetic acid (0.108 g) using the method of Example 94. Yield 0.15 g as a solid.

MS: APCI(+ve) 395 (M+1)

¹H NMR: δ (DMSO-d6) 7.98(d, 1H), 7.57(d, 1H), 7.53(d, 1H), 7.30-7.25(m, 3H), 7.13-7.07(m, 2H), 3.54-3.48(m, 1H), 3.45(s, 2H), 3.37(s, 2H), 2.72-2.69(m, 2H), 2.02(t, 2H), 1.71-1.68(m, 2H), 1.44-1.34(m, 2H).

MP: 144-7° C.

Example 100 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-[2-(2-pyrazinyl)-1,3-thiazol-4-yl]acetamide

The title compound was prepared from the product of Example 1 step (ii) (0.3 g) and 2-[2-(2-pyrazinyl)-1,3-thiazol-4-yl]acetic acid (0.155 g) using the method of Example 94. Yield 0.08 g as a solid.

MS: APCI(+ve) 462 (M+1)

¹H NMR: δ (DMSO-d6) 9.25(d, 1H), 8.74-8.71(m, 2H), 8.07(d, 1H), 7.64(s, 1H), 7.59-7.54(m, 2H), 7.31-7.28(m, 1H), 3.69(s, 2H), 3.59-3.54(m, 1H), 3.45(s, 2H), 2.74-2.71(m, 2H), 2.04(t, 2H), 1.76-1.74(m, 2H), 1.49-1.39(m, 2H).

MP: 186-9° C.

Example 101 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-[(5-phenyl-2-pyrimidinyl)sulfanyl]acetamide

The title compound was prepared from the product of Example 1 step (ii) (0.3 g) and 2-[(5-phenyl-2-pyrimidinyl)sulfanyl]acetic acid (0.172 g) using the method of Example 94. Yield 0.115 g as a solid.

MS: APCI(+ve) 487/9 (M+1)

¹H NMR: δ (DMSO-d6) 8.96(s, 2H), 8.09(d, 1H), 7.78-7.75 (m, 2H), 7.58-7.43(m, 5H), 7.28(dd, 1H), 3.91(s, 2H), 3.59-3.52(m, 1H), 3.44(s, 2H), 2.70(br d, 2H), 2.03(br t, 2H), 1.72(br d, 2H), 1.47-1.38(m, 2H).

MP: 157° C.

Example 102 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-3-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanamide

The title compound was prepared from the product of Example 1 step (ii) (0.9 g) and 3-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanoic acid (0.3 g) using the method of Example 94. Yield 0.074 g as a solid.

MS: APCI(+ve) 460/2 (M+1)

¹H NMR: δ (DMSO-d6) 8.76-8.74(m, 1H), 8.05-7.99(m, 2H), 7.94(d, 1H), 7.61-7.56(m, 2H), 7.52(d, 1H), 7.28(dd, 1H), 3.56-3.48(m, 1H), 3.43(s, 2H), 3.19(t, 2H), 2.71-2.66(m, 4H), 2.03(t, 2H), 1.69(br d, 2H), 1.42-1.33(m, 2H).

MP:155° C.

Example 103 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-1H-benzimidazol-2-amine

(i) Ethyl 4-(1H-benzimidazol-2-ylamino)-1-piperidinecarboxylate

A solution of 2-chlorobenzimidazole (1 g) and ethyl 4-amino-1-piperidinecarboxylate (2 g) in 1-methyl-2-pyrrolidinone was heated at 130° C. for 24 h. The mixture was partitioned between water and ethyl acetate, the organic layer washed with water, dried and evaporated under reduced pressure. Purification was by chromatography eluting with 1% triethylamine/5% methanol in dichloromethane. Yield 0.630 g as a solid.

TOF MS ES+ 289.1652 (M+1)

(ii) N-(4-Piperidinyl)-1H-benzimidazol-2-amine, dihydrochloride salt

The product from step (i) (0.58 g) was heated under reflux with 5M hydrochloric acid (20 ml) for 24 h. The solvent was evaporated under reduced pressure, the residue azetroped with toluene, washed with ether. Yield 0.58 g as a solid.

TOF MS ES+ 217.1452 (M+1)

(iii) N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-1H-benzimidazol-2-amine

Triethylamine (0.223 ml) was added to a stirred suspension of the product from step (ii) (0.2 g) in dimethylformamide. After 5 min 3,4-dichlorobenzaldehyde (0.175 g) then sodium triacetoxyborohydride (0.212 g) was added and the mixture stirred at room temperature for 3 h. The mixture was partitioned between 2M hyrochloric acid and ether, the aqueous layer was basified with aqueous sodium hydrogencarbonate and extracted with ethyl acetate. The organic layer was dried and evaporated under reduced pressure. The residue was triturated with ethyl acetate/ether and the solid collected. Yield 0.045 g.

TOF MS ES+ 375.4257 (M+1)

¹H NMR: δ (DMSO-d6) 10.6(br s, 1H), 7.60-7.56(m, 2H), 7.32(dd, 1H), 7.12-7.09(m, 2H), 6.86-6.83(m, 2H), 6.49(d, 1H), 3.55-3.49(m, 3H), 2.79-2.71(m, 2H), 2.13-1.91(m, 4H), 1.56-1.46(m, 2H).

MP: 125° C.

Example 104 2-{[1-(3,4-Dichlorobenzyl)-4-piperidinyl]amino}-N-(3-methoxyphenyl)acetamide, dihydrochloride Salt

2-Chloro-N-(3-methoxyphenyl)-acetamide (0.241 g) was added to a stirred solution of the product of Example 1 step (ii) (dihydrochloride salt) (0.4 g), triethylamine (0.608 g) in 1-methyl-2-pyrrolidinone (5 ml). The reaction mixture was heated at 80° C. for 6 h then partitioned between ethyl acetate and brine. The organic layer was washed with brine, dried and evaporated under reduced pressure. Purification was by chromatography eluting with chloroform/isohexane/triethylamine/methanol 30:15:3:0.5. The resulting product was converted to the hydrochloride salt using ethereal hydrogenchloride. Yield 0.135 g.

TOF MS ES+ 422.1406 (M+1)

¹H NMR: δ (DMSO-d6) 11.21(br s, 1H), 10.82(s, 1H), 9.53(br s, 2H), 7.95(s, 1H), 7.75(d, 1H), 7.60(d, 1H), 7.31-7.23(m, 2H), 7.15(d, 1H), 6.70(dd, 1H), 4.28(br s, 2H), 3.97(br, H), 3.73(s, 3H), 2.96(br, 2H), 2.28-2.05(m, 4H).

MP: 274-6° C.

Example 105 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N′-(3,4-dichlorophenyl)urea

3,4-Dichlorophenyl isocyanate (0.081 g) was added to a stirred solution of the product from Example 1 step (ii) (0.13 g), diisopropylethylamine (0.2 g) in dichloromethane (4 ml). The reaction mixture was stirred for 20 h and the solvent removed under reduced pressure. Purification was by chromatography eluting with 5% methanol/dichloromethane. Yield 0.09 g as a solid.

TOF MS ES+ 446.0360 (M+1)

¹H NMR: δ (DMSO-d6) 8.65(s, 1H), 7.82(d, 1H), 7.59(d, 1H), 7.54(s, 1H), 7.31(d, 1H), 7.22(dd, 1H), 6.26(d, 1H), 3.45(br s, 3H), 2.67(m, 2H), 2.11(m, 2H), 1.81(m, 2H), 1.40(m, 2H).

MP: 189-190° C.

Example 106 N-[1-(3,4-Dichlorobenzyyl)-4-piperidinyl]-N′-(3-methoxyphenyl)urea

3-Methoxyphenyl isocyanate (0.064 g) was added to a stirred solution of the product from Example 1 step (ii) (0.13 g), diisopropylethylamine (0.2 g) in dichloromethane (4 ml). The reaction mixture was stirred for 20 h and the solvent removed under reduced pressure. Purification was by chromatography eluting with 5% methanol/dichloromethane. Yield 0.09 g as a solid.

MS: APCI(+ve) 408/10 (M+1)

¹H NMR: δ (DMSO-d6) 8.32(s, 1H), 7.59(d, 1H), 7.55(d, 1H), 7.31(dd, 1H), 7.13(m, 1H), 7.09(d, 1H), 6.83(dd,1H), 6.47(dd, 1H), 6.09(d, 1H), 3.69(s, 3H), 3.46(m, 3H), 2.66(m, 2H), 2.13(m, 2H), 1.81(m, 2H), 1.42(m, 2H).

MP: 178°-9° C.

Example 107 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-N-(4-methoxybenzyl)amine, dihydrochloride Salt

The title compound was prepared from the product of Example 1 step (ii) (0.185 g) and 4-methoxybenzaldehyd3 (0.49 ul) using the method of Example 1 step (i). Yield 0.84 g as a solid.

MS: APCI(+ve) 379/81 (M+1)

¹H NMR: δ (DMSO-d6) 11.33(br s, 1H), 9.56(br s, 2H), 7.96 (s, 1H), 7.74(d, 1H), 7.61(d, 1H), 7.52(d, 1H), 6.97(d, 1H), 4.27(s, 2H), 4.07(s,2H), 3.77(s, 3H), 3.39-2.94(m, 5H), 2.32-2.28(m, 2H), 2.15-2.07(m, 2H).

MP: >250° C.

The following table lists Examples 108-348 which are of compounds of formula (I) all of which accord to formula (Ib).

(Ib)

Example R¹ (Q)_(m) n R⁶ 108 phenyl m = 0 2 3,4-Cl₂—C₆H₃ 109 4-Br—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 110 4-NH₂—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 111 2-Br—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 112 4-F—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 113 3-CH₃—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 114 2-CH₃—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 115 3-Cl-4-OH—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 116 2-NO₂—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 117 2-Cl—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 118 4-Cl—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 119 3,4-(OH)₂—C₆H₃ m = 0 2 3,4-Cl₂—C₆H₃ 120 4-NO₂—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 121 phenyl m = 0 4 3,4-Cl₂—C₆H₃ 122 3,4-(OCH₃)₂—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 123 3-F-4-OH—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 124 3,4-methylenedioxyphenyl m = 0 1 3,4-Cl₂—C₆H₃ 125 4-OH—C₆H₄ m = 0 2 3,4-Cl₂—C₆H₃ 126 4-OH—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 127 4-phenyl-phenyl m = 0 1 3,4-Cl₂—C₆H₃ 128 3,4-Cl₂—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 129 3-OH—C₆H₄ m = 0 2 3,4-Cl₂—C₆H₃ 130 4-CH₃—C₆H₄ m = 0 2 3,4-Cl₂—C₆H₃ 131 4-NO₂—C₆H₄ m = 0 3 3,4-Cl₂—C₆H₃ 132 3,4-(OCH₃)₂—C₆H₃ m = 0 2 3,4-Cl₂—C₆H₃ 133 C₆F₅ m = 0 2 3,4-Cl₂—C₆H₃ 134 4-CH₃—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 135 4-OCF₃—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 136 3,4-(OCH₃)₂—C₆H₃ m = 0 3 3,4-Cl₂—C₆H₃ 137 4-OCH₃—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 138 4-N(CH₃)₂—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 139 4-OCH₃—C₆H₄ m = 0 2 3,4-Cl₂—C₆H₃ 140 3,4,5-(OCH₃)₃—C₆H₂ m = 0 1 3,4-Cl₂—C₆H₃ 141 3,4-methylenedioxyphenyl m = 0 2 3,4-Cl₂—C₆H₃ 142 3-NH₂—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 143 naphth-1-yl m = 0 1 3,4-Cl₂—C₆H₃ 144 3-OCH₃-4-OH—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 145 3-(6-Br-1-(prop-2-en-1- m = 0 1 3,4-Cl₂—C₆H₃ yl)-naphth-2- yloxymethyl)phenyl 146 4-(4-NO₂—C₆H₄—CH₂O)— m = 0 1 3,4-Cl₂—C₆H₃ C₆H₄ 147 3-F-4-CH₃O—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 148 3-CH₃—C₆H₄ m = 0 4 3,4-Cl₂—C₆H₃ 149 3-OH—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 150 4-(C₆H₅—CH₂O)—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 151 4-(3-NO₂—C₆H₄)—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 152 2,5-(CH₃)₂—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 153 4-I—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 154 3-Br—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 155 2-CH₃-3-NO₂—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 156 3-OH-4-OCH₃—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 157 3-F—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 158 2-F—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 159 3,5-(OCH₃)₂—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 160 3-Cl—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 161 phenyl m = 0 1 3,4-Cl₂—C₆H₃ 162 3,5-(CH₃)₂—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 163 3-OCH₃—C₆H₄ m = 0 2 3,4-Cl₂—C₆H₃ 164 2,4-F₂—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 165 2-OCH₃—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 166 3,4-F₂—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 167 3,5-F₂—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 168 Pyridin-3-yl m = 0 1 3,4-Cl₂—C₆H₃ 169 Pyridin-2-yl m = 0 1 3,4-Cl₂—C₆H₃ 170 5-Br-pyridin-3-yl m = 0 1 3,4-Cl₂—C₆H₃ 171 2,4-(OCH₃)₂—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 172 4-(benzyloxy)phenyl m = 0 1 3,4-Cl₂—C₆H₃ 173 3-(benzyloxy)phenyl m = 0 1 3,4-Cl₂—C₆H₃ 174 2-methyl-naphth-1-yl m = 0 1 3,4-Cl₂—C₆H₃ 175 2-CH₃CH₂O—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 176 3,4-(OCH₃)₂—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 177 4-CH₃(CH₂)₃O—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 178 Indol-1-yl m = 0 1 3,4-Cl₂—C₆H₃ 179 2-NO₂—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 180 Thien-2-yl m = 0 1 3,4-Cl₂—C₆H₃ 181 3-Cl-4-OH—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 182 2,4-Cl₂—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 183 2,6-Cl₂—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 184 2-Br—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 185 3,4-Cl₂—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 186 3-Br—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 187 3,5-F₂—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 188 3-NH₂—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 189 2-(ClCH₂C(O)NH)- m = 0 1 3,4-Cl₂—C₆H₃ thiazol-4-yl 190 3-Cl—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 191 2,5-(OCH₃)₂—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 192 4-OH—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 193 Indol-3-yl m = 0 1 3,4-Cl₂—C₆H₃ 194 5-OCH₃-indol-3-yl m = 0 1 3,4-Cl₂—C₆H₃ 195 Naphth-2-yl m = 0 1 3,4-Cl₂—C₆H₃ 196 4-CH₃—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 197 3,4,5-(OCH₃)₃—C₆H₂ m = 0 1 3,4-Cl₂—C₆H₃ 198 4-CH₃(CH₂)₃O—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 199 4-S(O)₂CH₃—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 200 2,4,6-(CH₃)₃—C₆H₂ m = 0 1 3,4-Cl₂—C₆H₃ 201 4-F—C₆H₄ 202 2-(pyrazin-2-yl)-thiazol-4- m = 0 1 3,4-Cl₂—C₆H₃ yl 203 2-CH₃-5-(CH₃)₂CH-indol- m = 0 1 3,4-Cl₂—C₆H₃ 3-yl 204 5-(pyrrolidin-1-yl)- m = 0 1 3,4-Cl₂—C₆H₃ tetrazol-2-yl 205 5-(4-CH₃-phenyl)-tetrazol- m = 0 1 3,4-Cl₂—C₆H₃ 2-yl 206 3,5-F₂—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 207 3-OCH₃—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 208 5-Cl-benzo[b]thiophen-3- m = 0 1 3,4-Cl₂—C₆H₃ yl 209 3,4-Cl₂—C₆H₃ m = 0 1 3,4-Cl₂—C₆H₃ 210 2-phenyl-5-methyl-thiazol- m = 0 1 3,4-Cl₂—C₆H₃ 4-yl 211 4-OCF₃—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 212 3-methyl-5-Cl- m = 0 1 3,4-Cl₂—C₆H₃ benzo[b]thiophen-2-yl 213 3-methyl- m = 0 1 3,4-Cl₂—C₆H₃ benzo[b]thiophen-2-yl 214 2-NO₂—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 215 3-NO₂-1,2,4-triazol-1-yl m = 0 1 3,4-Cl₂—C₆H₃ 216 3,4-(NO₂)₂-5-CH₃- m = 0 1 3,4-Cl₂—C₆H₃ pyrazol-1-yl 217 4-(CH₃)₂CH(CH₂)₂O—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 218 2,3-(CH₃)₂-indol-5-yl m = 0 1 3,4-Cl₂—C₆H₃ 219 3,5-(CH₃)₂-4-Cl-pyrazol- m = 0 1 3,4-Cl₂—C₆H₃ 1-yl 220 3,5-(CH₃)₂-4-NO₂- m = 0 1 3,4-Cl₂—C₆H₃ pyrazol-1-yl 221 2,4-(NO₂)₂-imidazol-1-yl m = 0 1 3,4-Cl₂—C₆H₃ 222 4-NO₂-imidazol-1-yl m = 0 1 3,4-Cl₂—C₆H₃ 223 3,5-(CH₃)₂-pyrazol-1-yl m = 0 1 3,4-Cl₂—C₆H₃ 224 4-CH₃(CH₂)₅—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 225 2-CN—C₆H₄ m = 0 1 3,4-Cl₂—C₆H₃ 226 4-Cl—C₆H₄ O 1 4-Cl—C₆H₄ 227 4-Cl—C₆H₄ O 1 2-Br—C₆H₄ 228 4-Cl—C₆H₄ O 1 3-(CO₂CH₃)-4-Br—C₆H₄ 229 4-Cl—C₆H₄ O 1 4-NO₂—C₆H₄ 230 4-Cl—C₆H₄ O 1 3-benzoyl-phenyl 231 4-Cl—C₆H₄ O 1 5-OCH₃-benzimidazol-2-yl 232 4-Cl—C₆H₄ O 1 4-Br—C₆H₄ 233 4-Cl—C₆H₄ O 1 4-(1,2,3-thiadiazol-4-yl)-phenyl 234 4-Cl—C₆H₄ O 1 4-CH₃—C₆H₄ 235 4-Cl—C₆H₄ O 1 4-(2,6-Cl₂—C₆H₃)CH₂S(O)₂—C₆H₄ 236 4-Cl—C₆H₄ O 1 3,5-Br₂—C₆H₃ 237 4-Cl—C₆H₄ O 1 Indan-5-yl 238 4-Cl—C₆H₄ O 1 2-F-3-Cl—C₆H₃ 239 4-Cl—C₆H₄ O 1 benzofurazan-5-yl 240 4-Cl—C₆H₄ O 1 7-Cl-quinolin-2-yl 241 4-F—C₆H₄ m = 0 1 2,5-Cl₂—C₆H₃ 242 4-F—C₆H₄ m = 0 1 2,3-Cl₂—C₆H₃ 243 4-F—C₆H₄ m = 0 1 4-F—C₆H₄ 244 4-F—C₆H₄ m = 0 1 3-CO₂CH₃-4-Br—C₆H₃ 245 4-F—C₆H₄ m = 0 1 4-NO₂—C₆H₄ 246 4-F—C₆H₄ m = 0 1 3-benzoyl-phenyl 247 4-F—C₆H₄ m = 0 1 4-CH₃-naphth-1-yl 248 4-F—C₆H₄ m = 0 1 3,4-methylene-dioxyphenyl 249 4-F—C₆H₄ m = 0 1 5-OCH₃-benzimidazol-2-yl 250 4-F—C₆H₄ m = 0 1 3-NO₂-4-CH₃—C₆H₃ 251 4-F—C₆H₄ m = 0 1 3,4-(CH₃)₂—C₆H₃ 252 4-F—C₆H₄ m = 0 1 3-CH₃-4-OCH₃—C₆H₃ 253 4-F—C₆H₄ m = 0 1 4-(2-C(O)NH₂—C₆H₄)—C₆H₄ 254 4-F—C₆H₄ m = 0 1 4-Br—C₆H₄ 255 4-F—C₆H₄ m = 0 1 4-(2,6-Cl₂—C₆H₄)CH₂S(O)₂—C₆H₄ 256 3-(pyridin-2-yl)-1,2,4- m = 0 2 4-Cl—C₆H₄ oxadiazol-5-yl 257 3-(pyridin-2-yl)-1,2,4- m = 0 2 3-Cl-4-OCH₃—C₆H₃ oxadiazol-5-yl 258 3-(pyridin-2-yl)-1,2,4- m = 0 2 2,3-Cl₂—C₆H₃ oxadiazol-5-yl 259 3-(pyridin-2-yl)-1,2,4- m = 0 2 4-F—C₆H₄ oxadiazol-5-yl 260 3-(pyridin-2-yl)-1,2,4- m = 0 2 3-CF₃—C₆H₄ oxadiazol-5-yl 261 3-(pyridin-2-yl)-1,2,4- m = 0 2 4-NO₂—C₆H₄ oxadiazol-5-yl 262 3-(pyridin-2-yl)-1,2,4- m = 0 2 3-benzoyl-phenyl oxadiazol-5-yl 263 3-(pyridin-2-yl)-1,2,4- m = 0 2 3,4-methylene-dioxyphenyl oxadiazol-5-yl 264 3-(pyridin-2-yl)-1,2,4- m = 0 2 3,5-(CH₃)₂—C₆H₃ oxadiazol-5-yl 265 3-(pyridin-2-yl)-1,2,4- m = 0 2 3-NO₂-4-CH₃—C₆H₃ oxadiazol-5-yl 266 3-(pyridin-2-yl)-1,2,4- m = 0 2 3,4-(CH₃)₂—C₆H₃ oxadiazol-5-yl 267 3-(pyridin-2-yl)-1,2,4- m = 0 2 3-CH₃—C₆H₄ oxadiazol-5-yl 268 3-(pyridin-2-yl)-1,2,4- m = 0 2 3-CH₃-4-OCH₃—C₆H₄ oxadiazol-5-yl 269 3-(pyridin-2-yl)-1,2,4- m = 0 2 4-Br—C₆H₄ oxadiazol-5-yl 270 3-(pyridin-2-yl)-1,2,4- m = 0 2 Indan-5-yl oxadiazol-5-yl 271 3-(pyridin-2-yl)-1,2,4- m = 0 2 4-CF₃—C₆H₄ oxadiazol-5-yl 272 3-(pyridin-2-yl)-1,2,4- m = 0 2 Naphth-2-yl oxadiazol-5-yl 273 3-(pyridin-2-yl)-1,2,4- m = 0 2 4-CH₃—C₆H₄ oxadiazol-5-yl 274 3-(pyridin-2-yl)-1,2,4- m = 0 2 benzofurazan-5-yl oxadiazol-5-yl 275 3-(pyridin-2-yl)-1,2,4- m = 0 2 3,4-F₂—C₆H₃ oxadiazol-5-yl 276 3-(pyridin-2-yl)-1,2,4- m = 0 2 4-Cl-quinolin-2-yl oxadiazol-5-yl 277 3-(pyridin-2-yl)-1,2,4- m = 0 2 3-Cl—C₆H₄ oxadiazol-5-yl 278 3-(pyridin-2-yl)-1,2,4- m = 0 2 4-CF₃—C₆H₄ oxadiazol-5-yl 279 3-(pyridin-2-yl)-1,2,4- m = 0 2 4-CH₃—C₆H₄ oxadiazol-5-yl 280 4-OCH₃—C₆H₄ O 1 3,4-Cl₂—C₆H₃ 281 4-Cl—C₆H₄ O 1 3,4-Cl₂—C₆H₃ 282 4-NO₂—C₆H₄ O 1 3,4-Cl₂—C₆H₃ 283 4-NHC(O)CH₃—C₆H₄ O 1 3,4-Cl₂—C₆H₃ 284 4-O(CH₂)₂CH₃—C₆H₄ O 1 3,4-Cl₂—C₆H₃ 285 3-CO₂CH₂CH₃—C₆H₄ O 1 3,4-Cl₂—C₆H₃ 286 2-C(CH₃)₃—C₆H₄ O 1 3,4-Cl₂—C₆H₃ 287 2-NHC(O)CH₃—C₆H₄ O 1 3,4-Cl₂—C₆H₃ 288 3,5-(OCH₃)₂—C₆H₃ O 1 3,4-Cl₂—C₆H₃ 289 2-OCH₃-5-NO₂—C₆H₃ O 1 3,4-Cl₂—C₆H₃ 290 4-CN—C₆H₄ O 1 3,4-Cl₂—C₆H₃ 291 2-Cl-5-CF₃—C₆H₃ O 1 3,4-Cl₂—C₆H₃ 292 2-NO₂-5-CH₃—C₆H₃ O 1 3,4-Cl₂—C₆H₃ 293 3-Cl-5-OCH₃—C₆H₃ O 1 3,4-Cl₂—C₆H₃ 294 3-NO₂—C₆H₄ O 1 3,4-Cl₂—C₆H₃ 295 3-Br—C₆H₄ O 1 3,4-Cl₂—C₆H₃ 296 4-I—C₆H₄ O 1 3,4-Cl₂—C₆H₃ 297 3,5-F₂—C₆H₃ O 1 3,4-Cl₂—C₆H₃ 298 4,6-(NH₂)₂-pyrimidin-2-yl S 1 3,4-F₂—C₆H₃ 299 Benzimidazol-2-yl S 1 3,4-F₂—C₆H₃ 300 Thiazol-2-yl S 1 3,4-F₂—C₆H₃ 301

S 1 3,4-F₂—C₆H₃ 302 5-NO₂-benzimidazol-2-yl S 1 3,4-F₂—C₆H₃ 303 Pyridin-2-yl S 1 3,4-F₂—C₆H₃ 304

S 1 3,4-F₂—C₆H₃ 305 1H-1,2,4-triazol-3-yl S 1 3,4-F₂—C₆H₃ 306 Pyrimidin-2-yl S 1 3,4-F₂—C₆H₃ 307 1-phenyl-tetrazol-5-yl S 1 3,4-F₂—C₆H₃ 308 4,6-(CH₃)₂-pyrimidin-2-yl S 1 3,4-F₂—C₆H₃ 309 4-(thiophen-2-yl)- S 1 3,4-F₂—C₆H₃ pyrimidin-2-yl 310 2-(cyclopropyl-CH₂S)- S 1 3,4-F₂—C₆H₃ 1,3,4-thiadiazol-5-yl 311 4-methyl-3-(thiophen-2- S 1 3,4-F₂—C₆H₃ yl)-1,2,4-triazol-5-yl 312 3-CN-6-(CH₃C(O))- S 1 3,4-F₂—C₆H₃ pyridin-2-yl 313 1H-pyrazolo[3,4- S 1 3,4-F₂—C₆H₃ d]pyrimidin-4-yl 314 5-OCH₃-benzimidazol-2-yl S 1 3,4-F₂—C₆H₃ 315 5-F-6-Cl-benzimidazol-2-yl S 1 3,4-F₂—C₆H₃ 316 4,5-dihydrothiazol-2-yl S 1 3,4-F₂—C₆H₃ 317 1H-5-phenyl-1,2,4-triazol-3-yl S 1 3,4-F₂—C₆H₃ 318 2-(thiophen-2-yl)-1,3,4- S 1 3,4-F₂—C₆H₃ oxadiazol-5-yl 319 Quinoxalin-2-yl S 1 3,4-F₂—C₆H₃ 320 2,5-Cl₂—C₆H₃ S 1 3,4-F₂—C₆H₃ 321 2-(pyridin-2-yl)-1,3,4- S 1 3,4-F₂—C₆H₃ oxadiazol-5-yl 322 7-CF₃-quinolin-4-yl 323 2-(pyridin-2-yl)-4-CH₃- S 1 3,4-F₂—C₆H₃ pyrimidin-6-yl 324 Naphth-1-yl S 1 3,4-F₂—C₆H₃ 325 3,4-(OCH₃)₂—C₆H₃ S 1 3,4-F₂—C₆H₃ 326 1,3,4-thiadiazol-2-yl S 1 3,4-F₂—C₆H₃ 327 3-CF₃—C₆H₄ S 1 3,4-F₂—C₆H₃ 328

S 1 3,4-F₂—C₆H₃ 329 3,4-Cl₂—C₆H₃ S 1 3,4-F₂—C₆H₃ 330 3-CN-5-CH₃-pyridin-2-yl S 1 3,4-F₂—C₆H₃ 331 4-phenyl-thiazol-2-yl S 1 3,4-F₂—C₆H₃ 332

S 1 3,4-F₂—C₆H₃ 333 2-CH₃-1,3,4-thiadiazol-5-yl S 1 3,4-F₂—C₆H₃ 334

S 1 3,4-F₂—C₆H₃ 335

S 1 3,4-F₂—C₆H₃ 336 2-phenoxy-phenyl S 1 3,4-F₂—C₆H₃ 337 2-OCH₃—C₆H₄ S 1 3,4-F₂—C₆H₃ 338 2-CH₃-4-Cl—C₆H₃ S 1 3,4-F₂—C₆H₃ 339 2-CH₃-6-Cl—C₆H₃ S 1 3,4-F₂—C₆H₃ 340 2-(HC≡C—CH₂S)-1,3,4- S 1 3,4-F₂—C₆H₃ thiadiazol-5-yl 341 2-CO₂CH₃—C₆H₄ S 1 3,4-F₂—C₆H₃ 342 4-CN—C₆H₄ O 1 3,4-F₂—C₆H₃ 343 4-((CH₃)₂NCH₂)—C₆H₄ O 1 3,4-F₂—C₆H₃ 344

O 1 3,4-F₂—C₆H₃ 345 3-CH₂OH—C₆H₄ O 1 3,4-F₂—C₆H₃ 346 2-OCH₂CH₂OH—C₆H₄ O 1 3,4-F₂—C₆H₃ 347 4-CH₃(CH₂)₂O—C₆H₄ O 1 3,4-F₂—C₆H₃ 348 3-Cl-5-OCH₃—C₆H₃ O 1 3,4-F₂—C₆H₃

General Preparation of Examples 108-225

PyBroP® (bromo-tris-pyrrolidino-phosphonium hexafluorophosphate, 2 equivalents) was added to a solution of the product from Example 1 step (ii) (hydrochloride salt, 1 mg) the appropriate acid (2 equivalents) and triethylamine in 1-methyl-2-pyrrolidone (0.2 ml) and was left for 24 h. The reaction mixture was evaporated to dryness and the residue was dissolved in dimethylsulfoxide (0.3 ml).

General Preparation of Examples 225-240

Step i: tert-Butyl 4-{[(4-chlorophenoxy)acetyl]amino}-1-piperidinecarboxylate

Prepared following the method of Example 94 using (4-chlorophenoxy)acetic acid (0.50 g), 1,1-carbonyldiimidazole (0.50 g) and tert-butyl 4-amino-1-piperidinecarboxylate (0.46 g) to give the subtitle compound (0.54 g).

¹H NMR (399.978 MHz, CDCl₃) δ 1.34-1.40 (2H, m), 1.46 (9H, s), 1.90-1.95(2H, m), 2.86-2.88 (2H, m), 4.01-4.14 (3H, m), 4.45 (2H, s), 6.38-6.41 (1H, m), 6.84-6.87 (2H, m), 7.26-7.30 (2H, m).

Step ii: 2-(4-chlorophenoxy)-N-(4-piperidinyl)acetamide

Prepared following the method of Example 1 step (ii) using tert-butyl-4-{[(4-chlorophenoxy)acetyl]amino}-1-piperidinecarboxylate (0.52 g) to give the subtitle compound (0.35 g).

¹H NMR (399.978 MHz, CDCl₃) δ 1.32-1.45 (2H, m), 1.93-1.97 (2H, m), 2.68-2.77 (2H, m), 3.07-3.11 (2H, m), 3.91-4.04 (1H, m), 4.45 (2H, s), 6.38-6.40 (1H, m), 6.84-6.89 (2H, m), 7.26-7.31 (2H, m).

Step iii: Final product

A mixture of the product from step (ii) (1.07 mg), the appropriate alkyl halide (2 equivalents) and N,N-diisopropylethylamine (3 equivalents) in 1-methyl-2-pyrrolidinone (0.18 ml) was left at room temperature for 24 h. The mixture was evaporated to dryness and the residue was dissolved in dimethylsulfoxide (0.4 ml).

General Preparation of Examples 241-255

A mixture of 2-(4-fluorophenyl)-N-(4-piperidinyl)acetamide (WO97/36871; 0.94 mg), the appropriate alkyl halide (2 equivalents) and N,N-diisopropylethylamine (3 equivalents) in 1-methyl-2-pyrrolidinone (0.18 ml) was left at room temperature for 24 h. The mixture was evaporated to dryness and the residue was dissolved in dimethylsulfoxide (0.4 ml).

General Preparation of Examples 256-279

Step i: tert-Butyl 4-({3-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanoyl}amino)-1-piperidinecarboxylate

3-[3-(2-Pyridinyl)-1,2,4-oxadiazol-5-yl]propanoic acid (0.60 g) was dissolved in dichloromethane (10 ml). 1,1-Carbonyldiimidazole (0.33 g) was added followed by tert-butyl 4-amino-1-piperidinecarboxylate hydrochloride (0.5 g) and triethylamine (0.31 ml). After 2 hours water, brine and dichloromethane were added and the phases separated. The organic phase was dried, filtered and evaporated and the residue was purified by chromatography eluting with ethyl acetate:methanol (33:1) to give the subtitle compound (0.40 g).

¹H NMR (399.98 MHz, DMOS) δ 1.22-1.24 (2H, m), 1.39 (9H, s), 1.62-1.71 (2H, m), 2.66-2.71 (4H, m), 3.18-3.23 (2H, m), 3.65-3.83 (3H, m), 7.58-7.63 (1H), 8.01-8.04 (3H, m), 8.74-8.76(1H, m).

Step ii: N-(4-Piperidinyl)-3-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanamide

tert-Butyl 4-({3-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanoyl}amino)-1-piperidinecarboxylate (0.40 g) was dissolved in dichloromethane (6 ml) and trifluoroacetic acid (3 ml) was added. After 2 hours water, 2N sodium hydroxide and dichloromethane were added and the phases were separated. The organic phase was dried, filtered and evaporated to give the subtitle compound (0.19 g).

¹H NMR (399.978 MHz, CDCl₃) δ 1.35-1.45 (2H, m), 1.86-1.97 (2H, m), 2.69-2.84 (4H, m), 3.09-3.13 (2H, m), 3.32-3.36 (2H, m), 3.86-3.95 (1H, m), 5.82-5.84 (1H, m), 7.42-7.45 (1H, m), 7.83-7.87 (1H, m), 8.10-8.12 (1H, m), 8.78-8.79 (1H, m).

Step iii: Final product

A mixture of the product from step (ii) (1.21 mg), the appropriate alkyl halide (2 equivalents) and N,N-diisopropylethylamine (3 equivalent) in 1-methyl-2-pyrrolidinone (0.18 ml) was left at room temperature for 24 h. The mixture was evaporated to dryness and the residue was dissolved in dimethylsulfoxide (0.4 ml).

General Preparation of Examples 280-296

Step i: 2-Chloro-N-[1-(3,4-dichlorobenyzl)-4-piperidinyl]acetamide

Prepared following the general preparation method of Examples 297-357 step (iii) using 1-(3,4-dichlorobenzyl)-4-piperidinamine hydrochloride (2.0 g), N,N-diisopropylethylamine (5.55 ml) and chloroacetyl chloride (0.55 ml) to give the subtitle compound (1.0 g).

¹H NMR (399.978 MHz, CDCl₃) δ 1.48-1.61 (2H, m), 1.91-1.94 (2H, m), 1.95-2.18 (2H, m), 2.77-2.80 (2H, m), 3.44 (2H, s), 3.78-3.87 (1H, m), 4.04 (2H, s), 7.13-7.16 (1H, m), 7.37-7.43 (2H, m).

Step ii: Final Product

A mixture of the product from step (i) (1.34 mg), the appropriate phenol (1.5 equivalents) and potassium tert-butoxide (1.4 equivalents) in 1-methyl-2-pyrrolidinone (0.13 ml) was left at room temperature for 24 hours. The mixture was evaporated to dryness and the residue was dissolved in dimethylsulfoxide (0.4 ml).

General Preparation of Examples 297-340

Step i: Carbamic acid, [1-[(3,4-difluorophenyl)methyl]-4-piperidinyl]-, 1,1-dimethylethyl ester

Carbamic acid, 4-piperidinyl-, 1,1-dimethylethyl ester (6.95 g) was dissolved in N,N-dimethylformamide (70 ml). 3,4-Difluorobenzylbromide (4.55 ml) and potassium carbonate (16.0 g) were added. The mixture was heated to reflux for 16 hours, then allowed to cool to room temperature. Ammonium chloride solution was added and the mixture was extracted thrice with ethyl acetate. The organic phases were washed with water (twice) and brine, then dried, filtered and evaporated. The residue was triturated with ether:iso-hexane (1:1) to give the subtitle compound (8.13 g)

¹H NMR (399.978 MHz, CDCl₃) δ 1.36-1.43 (m, 2H), 1.44 (s, 9H), 1.91 (d, J=11.8 Hz, 2H), 2.08 (td, J=11.4, 2.7 Hz, 2H), 2.75 (d, J=11.3 Hz, 2H), 3.41 (s, 2H), 3.42-3.55 (m, 1H), 4.38-4.47 (m, 1H), 6.96-7.02 (m, 1H), 7.04-7.11 (m, 2H), 7.13-7.19 (m, 1H)

Step ii: 1-[(3,4-Difluorophenyl)methyl]-piperidin-4-ylamine dihydrochloride

Carbamic acid, [1-[(3,4-difluorophenyl)methyl]-4-piperidinyl]-, 1,1-dimethylethyl ester was suspended in 6N hydrochloric acid (100 ml). After 16 hours excess hydrochloric acid was evaporated and the residue azeotroped with toluene, dried and evaporated to give the subtitle compound (8.10 g).

¹H NMR (399.98 MHz, DMSO) δ 1.91-2.10 (2H, m), 2.31-2.47(2H, m), 2.86-3.20(2H,m), 3.54-3.66(3H,m), 4.75-4.83(2H,s), 7.26-7.61(3H,m).

Step iii: 2-Chloro-N-[1-[(3,4-difluorophenyl)methyl]-piperidin-4-yl]-acetamide

1-[(3,4-Difluorophenyl)methyl]-piperidin-4-ylamine dihydrochloride (3.18 g) was dissolved in tetrahydrofuran (40 ml). Diisopropylethlamine (6.84 g) and chloroacetyl chloride (1.33 g) were added. After 3 hours water, brine and ethyl acetate were added the phase were separated. The organic phase was dried, filtered and evaporated and the residue was purified by chromatography eluting with ethyl acetate to give the subtitle compound (0.728 g).

¹H NMR (CDCl₃) δ 1.46-1.59 (2H, m), 1.93 (2H, d), 2.14 (2H, td), 2.78 (2H, d), 3.43 (2H, s), 3.76-3.91 (1H, m), 4.04 (2H, s), 6.39-6.51 (1H, m), 6.98-7.02 (1H, m), 7.08 (1H, dd), 7.17 (1H, ddd).

Step iv: Final Product

The product from step (iii) (1.21 mg) was dissolved in dimethylsulfoxide (50 μl) and diisopropylethylamine (1.55 mg, 3 equivalents) was added as a solution in dimethylsulfoxide (50 μl). The appropriate thiol was added (1 equivalent) in dimethylsulfoxide (40 μl) and the reaction mixture was left at room temperature for 24 hours. The reaction mixture was evaporated to dryness and the residue was dissolved in dimethylsulfoxide (400 μl).

General Preparation of Examples 341-348

Prepared from the product of general preparation for Examples 297-340 step (iii) and the appropriate phenol following the method of Examples 280-296 step (ii).

Example 351 3-[3-(4-Bromo-1-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-5-yl]-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]propanamide

Step i: Methyl 4-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-4-oxobutanoate

To a solution of 1-(3,4-dichlorobenzyl)-4-piperidinamine hydrochloride (3.50 g) in dichloromethane (100 ml) was added methyl 4-chloro-4-oxobutanoate (2.00 g) dropwise. Triethlamine (3.90 g) was added and the reaction stirred under nitrogen for 2 hours. Saturated sodium hydrogen carbonate solution was then added, with the solution being extracted three times with dichloromethane. The pooled organic phase was washed once with water, once with saturated brine and dried over anhydrous magnesium sulfate. After filtration the solvent was removed under reduced pressure to leave methyl 4-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-4-oxobutanoate (3.00 g).

MS (+veES) 373 ((M+H)⁺)

Step ii: Lithium 4-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-4-oxobutanoate

To a solution of methyl 4-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-4-oxobutanoate (3.72 g) in methanol (30 ml) was added lithium hydroxide (0.41 g) in water (10 ml) which was stirred under nitrogen for 48 hours. The solvent was removed under reduced pressure, the residue was triturated with ether and filtered to leave lithium 4-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-4-oxobutanoate (3.50 g).

MS (+veES) 359 ((M+H)⁺)

Step iii: 3-[3-(4-Bromo-1-methyl-1H-pyrazol-3-yl)-1,2,4-oxadiazol-5-yl]-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]propanamide

To lithium 4-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-4-oxobutanoate (0.292 g) in dichloromethane (6 ml) was added dimethylformamide (1.5 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.183 g), 1-hydroxybenzotriazole hydrate (0.130 g), 4-bromo-N′-hydroxy-1methyl-1H-pyrazole-3-carboximidamide (0.175 g) and triethylamine (0.161 g). Reaction was left to stir for 24 hours before removal of dichloromethane under reduced pressure. Pyridine (5 ml) was added and heated at reflux for 5 hours. Pyridine was removed under reduced pressure, followed by the addition of water. The solution was extracted three times with dichloromethane. The pooled organic phase was washed once with water, once with saturated brine and dried over magnesium sulfate. After filtration the product was azeotroped twice with toluene and was purified by reverse phase hplc (RPHPLC; 75%-5% 0.1% ammonium acetate/acetonitrile). Solvent was removed under reduced pressure to give the title compound (0.164 g).

MS (+veAPC) 543 ((M+H)⁺)

¹H NMR (DMSO): δ 8.21-8.17 (1H,m); 7.95-7.76(1H,m); 7.60-7.54(1H,m); 7.35-7.25(1H,m); 4.35-4.21(1H,m); 3.93(2H,s); 3.44-3.35(2H,m); 3.19-3.14(3H,m); 2.73-2.64(2H,m); 2.58(3H,s); 2.00-1.89(2H,m); 1.73-1.60(2H,m); 1.36-1.24(1H,m).

Example 352 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-3-[3-(2-pyrazinyl)-1,2,4-oxadiazol-5-yl]propanamide

To lithium 4-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}-5-oxobutanoate (Example 351, step ii) (0.292 g) in dichloromethane (6 ml) was added N,N-dimethylformamide (1.5 ml), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.183 g), 1-hydroxybenzotriazole hydrate (0.130 g), N′-hydroxy-2-pyrazinecarboximidamide (0.110 g) and triethylamine (0.161 g). The reaction mixture was left to stir for 24 hours before removal of dichloromethane under reduced pressure. Pyridine (5 ml) was added and heated at reflux for 5 hours. Pyridine was removed under reduced pressure followed by the addition of water. The solution was extracted three times with dichloromethane. The pooled organic phase was washed once with water, once with saturated brine and dried over magnesium sulfate. After filtration the product was azeotroped twice with toluene and was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile). Solvent was removed under reduced pressure to give the title compound (0.067 g).

MS (+veAPC)461 ((M+H)⁺)

¹H NMR (DMSO) δ 9.23 (1H,s); 8.81-8.45(2H,m), 7.96-7.94(1H,m); 7.58-7.56(1H,m); 7.53-7.52(1H,m); 7.29-7.26(1H,m), 3.55-3.48(1H,m); 3.43(2H,s); 3.24-3.20(2H,m); 2.71-2.68(4H,m); 2.03-1.98(2H,m); 1.70-1.68(2H,m); 1.42-1.33(2H,m).

Example 353 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-3-{3-[2-thienylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl}propanamide Hydrochloride

Step i: 3-{3-[(2-Thienylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl}propionic acid

(1Z)-N′-hydroxy-2-(2-thienylsulfonyl)ethanimidamide (0.250 g) with dihydro-2,5-furandione (0.114 g) in dimethylformamide (0.2 ml) was heated at 120° C. for 2 hours. The reaction was allowed to cool and triturated with diethyl ether and filtered to leave 3-{3-[(2-thienylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl}propanoic acid (0.332 g).

MS (+veES) 303 ((M+H)⁺)

Step ii: N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-3-{3-[(2-thienylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl}propanamide hydrochloride

3-{3-[(2-Thienylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl}propanoic acid (0.332 g) in dichloromethane was stirred under nitrogen. Oxazolyl chloride (0.252 g) was added dropwise followed by the addition of one drop of dimethylformamide. After 30 minutes the solvent and oxalyl chloride was removed under reduced pressure followed by the addition of dichloromethane (10 ml), 1-(3,4-dichlorobenzyl)-4-piperidinamine hydrochloride (0.347 g), and triethylamine (0.202 g) and allowed to stir for 2 hours under nitrogen. Saturated sodium hydrogen carbonate was added to the reaction with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave a brown oil. This oil was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile) followed by chromatography using 3% ethanol/dichloromethane. The solvent was removed under reduced pressure, followed by the addition of hydrogen chloride in diethyl ether, filtered and dried to leave N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-3-{3-[(2-thienylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl}propanamide hydrochloride (0.04 g) as a pale yellow solid.

MS (+veES) 545 ((M+H)⁺)

¹H NMR (DMSO) δ 10.51(1H,s); 8.21-8.13(2H,m); 7.91(1H,s): 7.77-7.71(2H,m); 7.58-7.55(1H,m); 7.28-7.26(1H,m); 5.07-5.05(2H,m); 4.26-4.25(2H,m); 3.91(1H,m); 3.34-3.31(2H,m); 3.15-3.08(2H,m); 3.02-2.94(2H,m); 2.60-2.58(2H,m); 1.92-1.84(2H,m); 1.80-1.70(2H,m).

Example 354 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-3-[3-(4-pyridinyl)-1,2,4-oxadiazol-5-yl]propanamide

Step i: 3-[3-(4-Pyridinyl)-1,2,4-oxadiazol-5-yl]propanoic acid

N′-hydroxy-4-pyridinecarboximidazole (0.300 g) with dihydro-2,5-furandione (0.217 g) in dimethylformamide (2 drops) was heated for 4 times 30 seconds in a CEM MARS 5 microwave at 100% of 300 W to leave a fused mass. The reaction was allowed to cool and triturated with ethanol and filtered to leave 3-[3-(4-pyridinyl)-1,2,4-oxadiazol-5-yl]propanoic acid (0.241 g).

MS (+veES) 220 ((M+H)⁺)

Step ii: N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-3-[3-(4-pyridinyl)-1,2,4-oxadiazol-5-yl]propanamide

For method refer to Example 353 step ii.

Purification was performed via chromatography (2.5% ethanol/dichloromethane). Solvent removed under reduced pressure to leave N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-3-[3-(4-pyridinyl)-1,2,4-oxadiazol-5-yl]propanamide (0.154 g) as a pale cream solid.

MS (+veES) 460 ((M+H)⁺)

¹H NMR (DMSO) δ 8.81-8.79(2H, m); 7.96-7.90(3H, m); 7.60-7.56(2H, m); 7.30-7.27(1H, m); 3.53-3.51(1H, m); 3.44(2H, s); 3.23-3.19(2H, m); 2.71-2.68(4H, m); 2.05-1.97(2H, m); 1.71-1.67(2H, m); 1.44-1.32(2H, m).

Example 355 Cis-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]cyclopropanecarboxamide

Step i: Cis-2-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]cyclopropanecarboxylic acid

N′-hydroxy-2-pyridinecarboximidamide (0.137 g) with 3-oxabicyclo[3.1.0]hexane-2,4-dione (0.112 g) in dimethylformamide (2 drops) was heated for 4 times 30 seconds in a CEM MARS 5 microwave at 100% of 300 W to leave a fused mass. The reaction was allowed to cool and triturated with diethyl ether and filtered to leave cis-2-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]cyclopropanecarboxylic acid (0.200 g).

MS (+veES) 232 ((M+H)⁺)

Step ii: Cis-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]cyclopropanecarboxamide

Cis-2-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]cyclopropanecarboxylic acid (0.139 g) and N,N′-carbonyldiimidazole (0.110 g) in dichloromethane was stirred under nitrogen for 1 hour. 1-(3,4-dichlorobenzyl)-4-piperidinamine hydrochloride (0.198 g), and triethylamine (0.121 g) was then added and allowed to stir for 24 hours under nitrogen. Saturated sodium hydrogen carbonate was added to the reaction with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave an oil. This oil was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile). The solvent was removed under reduced pressure to leave Cis-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]cyclopropanecarboxamide (0.054 g) as a white solid.

MS (+veES) 472 ((M+H)⁺)

¹H NMR (DMSO) δ 8.74-8.73(1H, m); 8.26-8.24(1H, m); 8.03-7.98(2H, m); 7.59-7.55(2H, m); 7.51(1H, s); 7.27-7.25(1H, m); 3.44-3.37(3H, m); 2.67-2.63(3H, m); 2.27-2.21(1H, m); 2.00-1.89(2H, m); 1.66-1.65(2H, m); 1.59-1.56(1H, m); 1.48-1.43(1H, m); 1.37-1.32(2H, m).

Example 356 Cis-N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-3-[3-(2-pyridinyl)-1H-1,2,4-triazol-5-yl]propanamide

Step i: 3-[3-(2-Pyridinyl)-1H-1,2,4-triazol-5-yl]propanoic acid

2-Pyridinecarbohydrazonamide (0.136 g) and dihydro-2,5-furandione (0.100 g) in 1 ml of dimethylacetamide was heated for 10 times 30 seconds in a CEM MARS 5 microwave at 100% of 300 W under nitrogen to leave 3-[3-(2-pyridinyl)-1H-1,2,4-triazol-5-yl]propanoic acid in 1 ml of dimethylacetamide.

MS (−veES) 217 ((M−H)⁺)

Step ii: N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-3-[3-(2-pyridinyl)-1,2,4-triazol-5-yl]propanamide

3-[3-(2-Pyridinyl)-1,2,4-triazol-5-yl]propanoic acid (0.218 g) in 1 ml dimethylacetamide) and N,N′-carbonyldiimidazole (0.250 g) in dichloromethane was stirred under nitrogen for 30 minutes. 1-(3,4-Dichlorobenzyl)-4-piperidinamine hydrochloride (0.316 g), and triethylamine (0.218 g) was then added and allowed to stir for 2 hours under nitrogen. 1M sodium hydroxide was added to the reaction with the resulting solution being washed three times with dichloromethane. The aqueous phase was acidified with glacial acetic acid, with the water/acetic acid being removed under reduced pressure. Water was then added and extracted three times with dichloromethane. The pooled organic phases were extracted once with water and the water removed under reduced pressure to leave a white solid. This was then triturated with diethyl ether/dichloromethane, filtered and was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile), solvent removed to leave N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-3-[3-(2-pyridinyl)-1H-1,2,4-triazol-5-yl]propanamide (0.02 g).

MS (+veES) 459 ((M+H)⁺)

¹H NMR (DMSO) δ 8.66-8.65(1H, m); 8.03-8.01(1H, m); 7.95-7.91(1H, m); 7.83-7.81(1H, m); 7.58-7.56(1H, m); 7.52(1H, m); 7.47-7.44(1H, m); 7.29-7.27(1H, m); 3.55-3.50(1H, m); 3.43(2H, s); 2.93-2.89(2H, m); 2.68-2.67(2H, m); 2.55-2.49(2H, m); 2.04-1.98(2H, m); 1.70-1.68(2H, m); 1.42-1.32(2H, m).

Example 357 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-(3-phenyl-1H-1,2,4-triazol-5-yl)acetamide

(3-Phenyl-1H-1,2,4-triazol-5-yl)acetic acid (0.020 g) and N,N′-carbonyl diimidazole (0.016 g) in dichloromethane was stirred under nitrogen for 3 minutes. 1-(3,4-Dichlorobenzyl)-4-piperidinamine hydrochloride (0.031 g) and triethylamine (0.036 g) was then added and allowed to stir for 1 hour under nitrogen. Saturated sodium hydrogen carbonate was added to the reaction with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to a white solid. This was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile). Saturated sodium hydrogen carbonate was added to the pooled collected fractions with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-(3-phenyl-1H-1,2,4-triazol-5-yl)acetamide(0.031 g).

MS (+veES) 444 ((M+H)⁺)

¹H NMR (DMSO) δ 8.18-8.15(1H, m); 7.98-7.95(2H, m); 7.59-7.54(2H, m); 7.49-7.41(3H, m); 7.31-7.29(1H, m); 3.63(2H, s); 3.57-3.47(1H, m); 3.45(2H, s); 2.74-2.70(2H, m); 2.08-2.01(2H, m); 1.77-1.74(2H, m); 1.48-1.38(2H, m).

Example 358 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-(5-phenyl-1,3,4-oxadiazol-2-yl)acetamide acetate

3-(5-Phenyl-1,3,4-oxadiazol-2-yl)propanoic acid (0.175 g) and N,N′-carbonyldiimidazole (0.148 g) in dichloromethane was stirred under nitrogen for 30 minutes. 1-(3,4-Dichlorobenzyl)-4-piperidinamine hydrochloride (0.263 g), and triethylamine (0.126 g) was then added and allowed to stir for 2 hours under nitrogen. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave a cream solid. This solid was purified by chromatography using 2.5% ethanol/dichloromethane. The solvent was removed under reduced pressure and was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile) followed by 1 ml of glacial acetic acid being added and the solvent removed under reduced pressure to leave N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-(5-phenyl-1,3,4-oxadiazol-2-yl)acetamide acetate (0.024 g).

MS (+veES) 445 ((M+H)⁺)

¹H NMR (DMSO) δ 8.31-8.29(1H, m); 7.98-7.96(2H, m); 7.66-7.54(5H, m); 7.31-7.29(1H, m); 3.92(2H, s); 3.57-3.56(1H, m); 3.46(2H, s); 2.74-2.71(2H, m); 2.07-2.02(2H, m); 1.78-1.75(2H, m); 1.47-1.39(2H, m).

Example 359 N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]acetamide

Step i: Lithium [3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]acetate

2-(5-Methyl-1,2,4-oxadiazol-3-yl)pyridine (0.150 g) was stirred at −78° C. in dry tetrahydrofuran under nitrogen. (1.6M) n-butyl lithium (0.757 ml) was added dropwise so as to maintain the temperature at −78° C. After 30 minutes carbon dioxide was passed through the solution and the reaction was allowed to return to room temperature. Once the reaction had reached room temperature, water (1 ml) was added and all solvents were removed under reduced pressure to leave a yellow solid. This solid was triturated with ethyl acetate and filtered to leave a pale yellow solid (0.150 g).

¹H HMR (DMSO+D₂O) δ 8.75-8.73(1H, m); 8.12-8.00(2H, m); 7.65-7.61(1H, m); 3.77(2H, s).

Step ii: N-[1-(3,4-Dichlorobenzyl)-4-piperidinyl]-2-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]acetamide

Lithium [3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]acetate (0.140 g), 1-(3,4-dichlorobenzyl)-4-piperidinamine (0.170 g), PyBroP™ (0.400 g) were stirred under nitrogen in dimethyl formamide (15 ml). N,N-Diisopropylethylamine (0.171 g) was added and left to stir for 2 hours. 1M sodium hydroxide was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave product plus dimethylformamide. Water was added which resulted in precipitation of the product. The product was filtered and was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile). After removal of the solvent under reduced pressure the resulting white solid was triturated with diethyl ether, filtered and dried to leave N-[1-(3,4-dichlorobenyzl)-4-piperidinyl]-2-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]acetamide (0.067 g). m.p. 145° C.

MS (+veES) 446 ((M+H)⁺)

¹H NMR (DMSO) δ 8.77-8.75(1H, m); 8.37-8.35(1H, m); 8.07-8.00(2H, m); 7.62-7.54(3H, m); 7.31-7.30(1H, m); 4.02(2H, s); 3.60-3.55(1H, m); 3.46(2H, s); 2.74-2.67(2H, m); 2.08-2.03(2H, m); 1.78-1.76(2H, m); 1.48-1.39(2H, m).

Example 360 N-[1-(4-Bromobenzyl)-4-piperidinyl]-2-(4-fluorophenyl)acetamide

2-(4-Fluorophenyl)-N-(4-piperidinyl)acetamide (WO97/36871; 1.00 g), 1-bromo-4-(bromomethyl)benzene (1.06 g) and potassium carbonate (0.877 g) in dimethylformamide (15 ml) were heated to 70° C., under nitrogen for 1 hour. Water was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave a cream solid. This solid was triturated with diethyl ether, filtered and recrystallised from ethanol/water to give water crystalline needles of N-[1-(4-bromobenzyl)-4-piperidinyl]-2-(4-fluorophenyl)acetamide. m.p. (+veES) 407 ((M+H)⁺)

¹H NMR (DMSO) δ 7.99-7.98(1H, m); 7.51-7.49(2H, m); 7.28-7.24(4H, m); 7.12-7.06(2H, m); 3.51-3.46(1H, m); 3.41(2H, s); 3.36(2H, s); 2.72-2.69(2H, m); 2.01-1.96(2H, m); 1.70-1.68(2H, m); 1.42-1.34(2H, m).

Example 361 2-(4-Fluorophenyl)-N-[1-(2-quinolinylmethyl)-4-piperidinyl]acetamide

2-(4-Fluorophenyl)-N-(4-piperidinyl)acetamide (WO97/36871; 0.05 g), 2-quinolinecarbaldehyde (0.033 g) and sodium triacetoxyborohydride (0.067 g) in dichloroethane (3 ml) were stirred under nitrogen for 24 hours. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure, triturated with diethyl ether/ethyl acetate and filtered to leave 2-(4-fluorophenyl)-N-[1-(2-quinolinylmethyl)-4-piperidinyl]acetamide (0.020 g).

MS (+veES) 378 ((M+H)⁺)

¹H NMR (DMSO) δ 8.34-8.31(1H, m); 8.02-7.94(3H, m); 7.75-7.71(1H, m); 7.63-7.55(2H, m); 7.28-7.25(2H, m); 7.13-7.08(2H, m); 3.74(2H, s); 3.57-3.50(1H, m); 3.30(2H, s); 2.79-2.76(2H, m); 2.16-2.11(2H, m); 1.73-1.70(2H, m); 1.48-1.39(2H, m).

Example 362 N-[1-(3-Chloro-4-fluorobenzyl)-4-piperidinyl]-3-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanamide

3-[3-(2-Pyridinyl)-1,2,4-oxadiazol-5-yl]propanoic acid (0.218 g) and N,N′-carbonyldiimidazole (0.194 g) were stirred in dichloromethane (10 ml) under nitrogen for 1 hour. 1-(3-Chloro-4-fluorobenzyl)-4-piperidinamine (JP 59101483; 0.242 g) was then added and left to stir for 24 hours. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure, triturated with ethyl acetate/ethanol and filtered to leave N-[1-(3-chloro-4-fluorobenzyl)-4-piperidinyl]-3-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanamide. m.p. 150° C.

MS (+veAPC) 444 ((M+H)⁺)

¹H NMR (DMSO) δ 8.75-8.74(1H, m); 8.05-7.99(2H, m); 7.95-7.93(1H, m); 7.61-7.58(1H, m); 7.48-7.45(1H, m); 7.37-7.30(1H, m); 7.30-7.26(1H, m); 3.53-3.51(1H, m); 3.42(2H, s); 3.21-3.17(2H, m); 2.71-2.66(4H, m); 2.02-1.96(2H, m); 1.70-1.67(2H, m); 1.42-1.33(2H, m).

Example 363 N-[1-(4-Chloro-3-fluorobenzyl)-4-piperidinyl]-3-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanamide

Step i: tert-Butyl 1-(4-chloro-3-fluorobenzyl)-4-piperidinylcarbamate

4-Chloro-3-fluorobenzaldehyde (0.793 g) and tert-butyl 4-piperidinylcarbamate (1.00 g) were stirred under nitrogen in dried tetrahydrofuran (25 ml). Sodium triacetoxyborohydride (1.266 g) was then added and left for 24 hours. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave tert-butyl 1-(4-chloro-3-fluorobenzyl)-4-piperidinylcarbamate (1.80 g) as a white solid.

MS (+veAPC) 343 ((M+H)⁺)

Step ii: 1-(4-Chloro-3-fluorobenzyl)-4-piperidine

tert-Butyl 1-(4-chloro-3-fluorobenzyl)-4-piperidinylcarbamate (1.80 g) in dichloromethane (20 ml) was stirred under nitrogen. Trifluoroacetic acid (5 ml) was then added dropwise and the reaction was left to stir for 2 hours. 1M sodium hydroxide was added to the reaction until basic, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure. Product purified by chromatography (5% ethanol/dichloromethane to 10% ethanol/dichloromethane) and solvent removed under reduced pressure to leave an oil which crystallised over the period of 48 hours. The resulting solid was triturated with diethyl ether and filtered to leave 1-(4-chloro-3-fluorobenzyl)-4-piperidinamine (0.500 g) as a white solid.

Step iii: N-[1-(4-Chloro-3-fluorobenzyl)-4-piperidinyl]-3-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanamide

3-[3-(2-Pyridinyl)-1,2,4-oxadiazol-5-yl]propanoic acid (0.136 g) and N,N′-carbonyldiimidazole (0.114 g) were stirred in dichloromethane (10 ml) under nitrogen for 1 hour. 1-(4-Chloro-3-fluorobenzyl)-4-piperidinamine (0.150 g) was then added and left to stir for 2 hours. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave an oil. This was triturated with diethyl ether which caused product the to crystallise. After filtration, the product was washed with diethyl ether and dried to N-[1-(4-chloro-3-fluorobenzyl)-4-piperidinyl]-3-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanamide. m.p. 132° C.

MS (+veES) 444 ((M+H)⁺)

¹H NMR (DMSO) δ 8.76-8.74(1H, m); 8.05-7.99(2H, m); 7.95-7.94(1H, m); 7.61-7.58(1H, m); 7.54-7.50(1H, m); 7.32-7.28(1H, m); 7.16-7.14(1H, m); 3.55-3.47 (1H, m); 3.44(2H, s); 3.21-3.17(2H, m); 2.71-2.66(4H, m); 2.03-1.97(2H, m); 1.70-1.67(2H, m); 1.42-1.33(2H, m).

Example 364 2-(4-Chlorophenoxy)-N-[1-[(3,4-dichlorophenyl)methyl]-piperidin-4-yl]-acetamide

The product from Example 1 step (ii) was dissolved in dichloromethane (10 ml) containing triethylamine (0.081 g) and the solution was cooled to 0° C. 4-Chlorophenoxyacetyl chloride (88 mg) in dichloromethane (3 ml) was added dropwise, the cooling bath was removed and the resulting solution was stirred for 1 hour. Ethyl acetate, water and brine were added and the phases were separated. The organic phase was dried, filtered and evaporated to give an oil which was purified by reverse phase HPLC (with a gradient eluent system (25% MeCN/NH₄OAc_(aq) (0.1%) to 95% MeCN/NH₄OAc_(aq) (0.1%)) to give the title compound (0.049 g).

¹H NMR: (CDCl₃): δ 1.51 (2H, ddd), 1.89-1.96 (2H, m), 2.15 (2H, td), 2.77 (2H, d), 3.43 (2H, s), 3.85-3.96 (1H, m), 4.44 (2H, s), 6.37 (1H, d), 6.85 (2H, dt), 7.14 (1H, dd), 7.26-7.29 (2H, m), 7.37 (1H, d), 7.43 (1H, d)

Example 365 N-(1-benzyl-4-piperidinyl)-3-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]propanamide

To a solution of 3-(3-Pyridin-2-yl-[1,2,4]oxadiazol-5-yl)-propionic acid (1 g) in tetrahydrofuran (5 ml), was added carbonyldiimidazole (0.74 g). The mixture was stirred for 10 minutes before addition of 1-benzyl-piperidin-4-ylamine (1 ml) in tetrahydrofuran (5 ml). The reaction mixture was stirred for 15 minutes then partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was separated, dried (MgSO₄) and solvent removed by evaporation. Purification by Biotage® 40S eluting 3%MeOH/0.5% 880 ammonia/dichloromethane gave the title compound (0.93 g).

MS:ESI 392 (+H)

¹H NMR (CDCl₃): δ 1.44 (2H, ddd), 1.88 (2H, d), 2.10 (2H, t), 2.73-2.78 (2H, m), 2.80 (2H, t), 3.33 (2H, t), 3.46 (2H, s), 3.75-3.86 (1H, m), 5.57 (1H, d), 7.23-7.32 (5H, m), 7.42 (1H, ddt), 7.84 (1H, tt), 8.10 (1H, dd), 8.79 (1H, td).

Example 366 N-(2-{[1-(3,4-Dichloro-benzyl)-piperidin-4-yl]-methyl-amino}-ethyl)-2-(2-fluoro-phenyl)-acetamide

Step i: (2-Methylamino-ethyl)-carbamic acid tert-butyl ester

To a solution of (2-amino-ethyl)-carbamic acid-tert-butyl ester (5 g) and triethylamine (6.5 ml) in tetrahydrofuran (1000 ml) at 0° C. was added methyliodide (1.94 ml) dropwise over a period of 1 hour. The mixture was allowed to warm to ambient temperature and stirred for 72 hours before removal of solvents by evaporation. The residue was partitioned between ethyl acetate and water. The organic layer was separated, dried (MgSO₄) and solvent removed by evaporation to give the title compound (3.7 g).

MS: ESI 57((CH₃)₄C+), 118 (M+H−(CH₃)₄C)

Step ii: (2-{[1-(3,4-Dichloro-benzyl)-piperidin-4-yl]-methyl-amino}-ethyl)-carbamic acid tert-butyl ester

To a solution of dichlorobenzyl-piperidin-4-one (Example 74, step (i), 4.8 g) and acetic acid (1 ml) in dichloromethane (100 ml) was added (2-methylamino-ethyl)-carbamic acid tert-butyl ester (3.26 g) and the mixture was stirred for 5 minutes before addition of sodium triacetoxyborohydride (7.9 g). The reaction mixture was stirred for 12 hours before addition of sodium bicarbonate solution. The mixture was stirred for ½ hour and then partitioned between water and dichloromethane. The organic layer was separated, dried (MgSO₄) and solvent removed by evaporation. Purification by Biotage® 40S eluting 10%MeOH/2% triethylamine/dichloromethane gave the title compound (1.7 g).

MS: ESI 316/318 (+H−(CH₃)₄COCO)

¹H NMR: (CDCl₃): δ 1.44 (9H, s), 1.50-1.60 (4H, m), 1.65-1.72 (2H, m), 1.95 (2H, td), 2.23 (3H, s), 2.34 (1H, tt), 2.88 (2H, d), 3.14-3.20 (2H, m), 3.41 (2H, s), 4.95-5.01 (1H, m), 7.13-7.15 (1H, m), 7.37 (1H, d), 7.42 (1H, d).

Step iii: N¹-[1-(3,4-Dichloro-benzyl)-piperidin-4-yl]-N¹-methyl-ethane-1,2-diamine (2-{[1-(3,4-Dichloro-benzyl)-piperidin-4-yl]-methyl-amino}-ethyl)-carbamic acid tert-butyl ester (1.7 g) was dissolved in 6M HCl (20 ml) and stirred for 12 hours. The solvent was evaporated and the residue was azeotroped with toluene and then sodium bicarbonate solution was added. The mixture was stirred for 10 minutes and the product was extracted with dichloromethane. The solvent was removed by evaporation to give the title compound (0.75 g).

MS: ESI 316/318 (+H)

Step iv: N-(2-{[1-(3,4-Dichloro-benzyl)-piperidin-4-yl]-methyl-amino}-ethyl)-2-(2-fluoro-phenyl)-acetamide Prepared by the method of Example 359 step (ii) using N¹-[1-(3,4-Dichloro-benzyl)-piperidin-4-yl]-N¹-methyl-ethane-1,2-diamine and 2-fluorophenylacetic acid.

MS: ESI 452/454 (+H)

¹H NMR: (CDCl₃): δ 2.08-1.94 (2H, m), 2.37-2.33 (2H, m), 2.95 (3H, s), 3.18 (2H, t), 3.41 (2H, m), 3.66-3.78(4H, m), 3.75 (2H, s), 3.84 (1H, m), 4.38 (2H, s), 7.16-7.28 (2H, m), 7.36-7.42 (2H, m), 7.45 (1H, d), 7.22 (1H, d).

Example 367 N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-N-methyl-2-(4-fluorophenyl)acetamide

Step i: [1-(3,4-Dichlorobenzyl)-piperidin-4-yl]-methyl-amine

To a solution of 1-(3,4-Dichloro-benzyl)-piperidin-4-one (3.1 g) in dichloromethane (50 ml) and acetic acid (0.69 ml) was added methylamine (6 ml of a 1M solution in tetrahydrofuran). The mixture was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (3 g) and the resulting mixture stirred for 72 hours. Sodium bicarbonate solution (100 ml) added and the mixture stirred vigorously for 5 minutes before extraction of the product with dichloromethane (2×200 ml). The organics were separated, bulked and dried, (MgSO₄). Purification by Biotage® 40S eluting 10%MeOH/0.5% 800 ammonia/dichloromethane gave the sub-title compound (1.8 g).

MS: ESI 273/275 (+H)

-   -   ¹H NMR: (CDCl₃): δ 1.36 (2H, qd), 1.82-1.91 (2H, m), 2.03 (2H,         td), 2.36 (1H, tt), 2.43 (3H, s), 2.76-2.83 (2H, m), 3.43 (2H,         s), 7.15 (1H, dd), 7.37 (1H, d), 7.42 (1H, d).         Step ii:         N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-(4-fluorophenyl)acetamide

To a solution of 4-fluorophenylacetic acid (100 mg) in tetrahydrofuran (3 ml) was added carbonyldiimidazole (105 mg). The mixture was stirred for 10 minutes before addition of [1-(3,4-dichlorobenzyl)-piperidin-4-yl]-methyl-amine (177 mg) in tetrahydrofuran (2 ml). Stirring was continued for 1 hour then solvent removed by evaporation. Purification by Biotage® 40S eluting 2%MeOH/0.5% 880 ammonia/dichloromethane gave the title compound (166 mg).

MS: ESI 273/275 (M+H)

¹H NMR: (CDCl₃) δ 1.57 (1H, d), 1.69 (1H, qd), 1.76-1.84 (1H, m), 1.88 (1H, q), 2.10 (2H, td), 2.85-2.90 (1H, m), 2.85 (3H, s), 3.42 (2H, s), 3.58 (1H, tt), 3.67 (2H, s), 4.51 (1H, tt), 7.00 (2H, t), 7.11-7.15 (1H, m), 7.18-7.23 (2H, m), 7.37 (1H, d), 7.41 (1H, dd).

Example 368 N-[1-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-2-(2-pyrimidinyloxy)-acetamide

Step i: Ethyl 2-pyrimidinyloxyacetate

Ethyl glycolate (1.04 g) was dissolved in tetrahydrofuran (10 ml) and the solution was cooled to 0° C. Sodium hydride (60% suspension in oil, 0.43 g) was added and the suspension was stirred and then sonicated in an ultrasonic bath. 2-Chloropyrimidine (1.14 g) was added and the mixture was sonicated for a further 110 min. Ammonium chloride solution was added and the mixture was extracted thrice with ethyl acetate, the organic phases were washed with brine and dried, filtered and evaporated. The residue was purified by chromatography eluting with iso-hexane:ethyl acetate (13:7) to give the subtitle compound (1.40 g) as an oil.

¹H NMR (299.944 MHz, CDCl₃) δ 1.26 (t, J=6.8 Hz, 3H), 4.24 (q, J=7.1 Hz, 2H), 4.93 (s, 2H), 6.98 (t, J=4.8 Hz, 1H), 8.53 (d, J=4.8 Hz, 2H).

Step ii: 2-Pyrimidinyloxyacetic acid

Ethyl 2-pyrimidinyloxyacetate (1.4 g) was dissolved in ethanol (10 ml). Sodium hydroxide (2M aq) was added and the mixture was stirred for 64 h. The solvent was evaporated and the residue was dissolved in water, filtered and the acidified with concentrated hydrochloric acid. The resulting precipitate was collected and dried to give the subtitle compound (0.698 g).

¹H NMR (399.98 MHz, DMSO) δ 4.85 (s, 2H), 7.09 (t, J=4.9 Hz, 1H), 8.56 (d, J=4.8 Hz, 2H).

Step iii: N-[1-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-2-(2-pyrimidinyloxy)-acetamide

The title compound was prepared from the product of Example 1 step (ii) (hydrochloride salt, 335 mg) and 2-pyrimidinyloxyacetic acid (170 mg) using the method of Example 94. Yield 140 mg. m.p. 120-122° C.

¹H NMR (399.978 MHz, CDCl₃) δ 1.50 (q, J=11.6 Hz, 2H), 1.91 (d, J=11.9 Hz, 2H), 2.13 (t, J=11.1 Hz, 2H), 2.77 (d, J=11.4 Hz, 2H), 3.42 (s, 2H), 3.86-3.95 (m ,1H), 4.87 (s, 2H), 6.49 (d, J=6.9 Hz, 1H), 7.05 (t, J=4.9 Hz, 1H), 7.14 (m, 1H), 7.37 (d, J=8.3 Hz, 1H), 7.42 (s, 1H), 8.57 (d, J=4.8 Hz, 2H).

Example 369 N-[2-[[8-[(3,4-Dichlorophenyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]amino]ethyl]-3-methoxy-benzamide, bis toluene sulfonic acid salt

Step i: 8-[(3,4-Dichlorophenyl)methyl]-8-azabicyclo[3.2.1]octan-3-one

2,5-Dimethoxytetrahydrofuran (4.92 g) was stirred in hydrochloric acid (1M, 25 ml) for 1 hour. 3,4-Dichlorobenzylamine (5 ml) was added to hydrochloric acid (1M, 15 ml) and the resulting suspension was added to the first solution. Phosphate buffer solution (pH 5.5, 250 ml) was added followed by sodium hydroxide (1.6 g). A solution of acetone dicarboxylic acid (4.77 g) in phosphate buffer solution (pH 5.5, 90 ml) was added to the mixture and the solution was stirred. A yellow solid formed and the mixture was left to stand for 64 h. The aqueous supernatant was decanted and hydrochloric acid (2.5M) was added to the solid along with ethyl acetate. The layers were separated and the aqueous phase was extracted twice with dichloromethane containing a little methanol. The organic layers were combined and evaporated to give a crude oil (ca 7 g). A portion of the product (ca 2.5 g) was purified by chromatography eluting with dichloromethane:methanol (19:1) to give the subtitle compound (1.62 g) as a yellow oil.

¹H NMR (299.944 MHz, CDCl₃) δ 1.62-1.70 (m, 2H), 2.09-2.15 (m, 2H), 2.23 (d, J=15.9 Hz, 2H), 2.67 (d, J=16.7 Hz, 2H), 3.43-3.49 (m, 2H), 3.68 (s, 2H), 7.26 (d, J=8.7 Hz, 1H), 7.41 (d, J=7.5 Hz, 1H), 7.54 (s, 1H)

Step ii: Carbamic acid, Endo-[2-[[8-[(3,4-dichlorophenyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]amino]ethyl]-1,1-dimethylethyl ester

8-[(3,4-Dichlorophenyl)methyl]-8-azabicyclo[3.2.1]octan-3-one (751 mg) and carbamic acid, (2-aminoethyl)-1,1-dimethylethyl ester (520 mg) were dissolved in dichloroethane (23 ml). Sodium triacetoxyborohydride (697 mg) was added and the suspension was stirred at room temperature for 20 hours. Dichloromethane was added and the solution was washed with sodium bicarbonate solution, then with water and then with brine. Chromatography of the residue eluting with ethyl acetate:methanol:triethylamine (80:19:1) gave the subtitle compound (688 mg) as an oil.

¹H NMR (399.978 MHz, CDCl₃) δ 1.45 (s, 9H), 1.52 (d, J=14.4 Hz, 2H), 1.96-2.09 (m, 6H), 2.67 (t, J=5.8 Hz, 2H), 2.88 (t, J=6.4 Hz, 1H), 3.08-3.12 (m, 2H), 3.21 (q, J=5.7 Hz, 2H), 3.48 (s, 2H), 4.80-4.95 (m, 1H), 7.22 (dd, J=8.3, 2.0 Hz, 1H), 7.37 (d, J=7.9 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H)

Step iii: N-[2-[[8-[(3,4-Dichlorophenyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]amino]ethyl]-3-methoxy-benzamide, bis toluene sulfonic acid salt

Carbamic acid, [2-[[8-[(3,4-dichlorophenyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]amino]ethyl]-,1,1-dimethylethyl ester (337 mg) was dissolved in dichloromethane (3 ml) and trifluoroacetic acid (3 ml) was added. The resulting solution was stirred for 1 hour then the volatiles were evaporated. The residue was dissolved in dichloromethane (3 ml) and triethylamine (1 ml) was added followed by 3-methoxybenzoyl chloride (120 μl). The solution was stirred overnight. The solvent was evaporated and the residue was purified by RPHPLC (gradient ammonium acetate 1% aqueous:acetonitrile (25% acetonitrile to 95% acetonitrile)). Excess tosic acid in ether was added to the residue and the resultant salt was recrystallised from a mixture of ethyl acetate-ethanol with a little cyclohexane to give the title compound (77 mg). m.p. 180-182.5° C.

¹H NMR (399.98 MHz, DMSO) δ 2.10-2.24 (m, 4H), 2.29 (s, 6H), 2.39-2.47 (m, 4H), 3.21-3.28 (m, 2H), 3.52-3.57 (m, 1H), 3.57-3.63 (m, 2H), 3.80 (s, 3H), 3.85-3.91 (m, 2H), 4.21 (d, J=5.4 Hz, 2H), 7.11 (d, J=9.4 Hz, 4H), 7.13-7.18 (m, 1H), 7.38-7.45 m, 3H), 7.48 (d, J=7.9 Hz, 4H), 7.56 (d, J=6.7 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.84-7.90 (m, 1H), 8.38-8.52 (m, 2H), 8.81-8.87 (m, 1H), 9.44-9.51 (m, 1H).

Example 370 Endo-N-[8-[(3,4-dichlorophenyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]-3-(2-pyridinyl)-1,2,4-oxadiazole-5-propanamide hydrochloride

Step i: Endo-8-[(3,4-dichlorophenyl)methyl]-8-azabicyclo[3.2.1]cctan-3-amine

8-[(3,4-Dichlorophenyl)methyl]-8-azabicyclo[3.2.1]octan-3-one (350 mg) was dissolved in dry methanol (12 ml) and ammonium acetate (1 g) was added. The mixture was stirred to get partial solution and then sodium cyanoborohydride (106 mg) was added. The mixture was heated under reflux for 150 minutes, then allowed to cool to room temperature. The methanol was evaporated, the residue was partitioned between sodium hydroxide and dichloromethane, and the aqueous phase was extracted twice with dichloromethane. The organic phases were combined, dried, filtered and evaporated to give the subtitle compound. [M+H]⁺ (ES+) 285

Step ii: Endo-N-[8-[(3,4-dichlorophenyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]-3-(2-pyridinyl)-1,2,4-oxadiazole-5-propanamide hydrochloride

3-(2-Pyridinyl)-1,2,4-oxadiazole-5-propanoic acid (305 mg) was suspended in dichloromethane (6 ml) and oxalyl chloride (0.5 ml) was added. The mixture was stirred overnight. Toluene (1 ml) was added to the solution, the volatiles were evaporated, then the residue was redissolved in dichloromethane (2 ml). Endo-8-[(3,4-dichlorophenyl)methyl]-8-azabicyclo[3.2.1]octan-3-amine (all from step(i)) was dissolved in dichloromethane (4 ml) containing triethylamine (0.5 ml) and then cooled in an ice bath. The acid chloride solution was added to the amine and the mixture was stirred for 1 hour. Water was added to the reaction mixture and the phases were separated. The aqueous phase was extracted twice with dichloromethane, the organic phases were dried, filtered and evaporated. The residue was purified by RPHPLC (gradient ammonium acetate 1% aqueous:acetonitrile (25% acetonitrile to 95% acetonitrile)). The product was suspended in ether and the ethereal hydrochloric acid was added, the suspension was stirred and then the diethyl ether was evaporated. The residue was dissolved in hot ethyl acetate containing ethanol and crystallisation was induced by adding iso-hexane to give the title compound (47 mg).

¹H NMR (399.98 MHz, DMSO) δ 1.99-1.90 (m, 2H), 2.41-2.20 (m, 6H), 2.77 (t, J=6.8 Hz, 2H), 3.23 (t, J=6.9 Hz, 2H), 3.81-3.72 (m, 3H), 4.15 (d, J=6.2 Hz, 2H), 7.63-7.58 (m, 1H, 7.67 (dd, J=7.6, 2.3 Hz, 2H), 7.76 (d, J=9.3 Hz, 1H), 8.06-7.99 (m, 3H), 8.11 (d, J=4.1 Hz, 1H), 8.75 (d, J=4.6 Hz, 1H), 10.13 (t, J=5.6 Hz, 1H).

Example 371 2-[4-(acetylamino)phenoxy]-N-[1-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-acetamide

Step i: Methyl (4-acetaminophenoxy)acetate

4-Acetaminophenol (1.51 g), potassium carbonate (1.38 g) and methyl bromoacetate (1.0 ml) were combined in acetone (40 ml) and heated to reflux for 5 hours. The mixture was allowed to cool to room temperature, filtered and evaporated. The residue was dissolved in ethyl acetate, washed with water and then with brine then dried, filtered and evaporated to give the subtitle compound (2.32 g).

¹H NMR (399.978 MHz, CDCl₃) δ 2.16 (s, 3H), 3.80 (s, 3H), 4.62 (s, 2H), 6.87 (d, J=9.1 Hz, 2H), 7.07 (br s, 1H), 7.40 (d, J=9.0 Hz, 2H)

Step ii: (4-Acetaminophenoxy)acetic acid

Methyl (4-acetaminophenoxy)acetate was hydrolysed following the method of Example 368 step (ii) to give the subtitle compound (1.85 g).

¹H NMR (399.98 MHz, DMSO) δ 2.00 (s, 3H), 4.61 (s, 2H), 6.84 (d, J=9.0 Hz, 2H), 7.46 (d, J=9.0 Hz, 2H), 9.80 (s, 1H).

Step iii: 2-[4-(acetylamino)phenoxy]-N-[1-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-acetamide

The title compound was prepared from the product of Example 1 step (ii) (free base, 281 mg) and (4-acetaminophenoxy)acetic acid (229 mg) using a method hereinbefore described (yield 40 mg). m.p. 177-178.5° C.

¹H NMR (299.946 MHz, DMSO) δ 1.51 (qd, J=10.5, 3.7 Hz, 2H), 1.72-1.63 (m, 2H), 2.00 (s, 3H), 2.05 (t, J=3.7 Hz, 2H), 2.77-2.68 (m, 2H), 3.45 (s, 2H), 3.70-3.57 (m, 1H), 4.39 (s, 2H), 6.88 (d, J=9.0 Hz, 2H), 7.29 (dd, J=8.1, 1.7 Hz, 1H), 7.47 (d, J=8.8 Hz, 2H), 7.54 (d, J=1.5 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H), 9.79 (s, 1H).

Example 372 N-[1-[(3,4-dichlorophenyl)methyl]-4-piperidinyl]-4-hydroxy-benzeneacetamide

The title compound was prepared from the product of Example 1 step (ii) (free base, 172 mg) and 4-hydroxyphenylacetic acid (135 mg) using a method hereinbefore described (yield 57 mg). m.p. 72-97° C.

¹H NMR (399.98 MHz, DMSO) δ 1.37 (q, J=7.0 Hz, 2H), 1.69 (d, J=11.3 Hz, 2H), 2.02 (t, J=5.3 Hz, 2H), 2.71 (d, J=11.3 Hz, 2H), 3.23 (s, 2H), 3.44 (s, 2H), 3.55-3.42 (m, 1H), 6.66 (d, J=8.5 Hz, 2H), 7.02 (d, J=8.5 Hz, 2H), 7.29 (d, J=8.2 Hz, 1H), 7.53 (s, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H), 9.18 (s, 1H).

Example 373 Exo-N-[8-[(3,4-dichlorophenyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]-3-(2-pyridinyl)-1,2,4-oxadiazole-5-propanamide

Step i: Endo-8-[(3,4-dichlorophenyl)methyl]-8-azabicyclo[3.2.1]octan-3-ol

8-[(3,4-Dichlorophenyl)methyl]-8-azabicyclo[3.2.1]octan-3-one (330 mg) was dissolved in tetrahydrofuran (5 ml) and cooled to 0° C. Lithium tris (3-ethylpentyl-3-oxy)aluminohydride solution (0.5M, 2.5 ml) was added dropwise and the mixture was allowed to attain room temperature overnight. Sodium sulfate decahydrate (ca 2 g) was added and the suspension was stirred for 1 hour. The reaction mixture was diluted with ethyl acetate, filtered through kieselguhr and evaporated. The residue was purified by chromatography eluting with dichloromethane:methanol (9:1) to give the subtitle compound 161 mg.

¹H NMR (399.978 MHz, CDCl₃) δ 1.59 (d, J=8.1 Hz, 2H), 1.64 (t, J=11.4 Hz, 2H), 1.86-1.81 (m, 2H), 2.00-1.97 (m, 2H), 3.21-3.18 (m, 2H), 3.55 (s, 2H), 3.95 (septet, J=5.6 Hz, 1H), 7.21 (d, J=8.2 Hz, 1H), 7.37 (d, J=7.4 Hz, 1H), 7.50 (s, 1H).

Step ii: Exo-2-[8-[(3,4-dichlorophenyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]-1H-isoindole-1,3(2H)-dione

Endo-8-[(3,4-dichlorophenyl)methyl]-8-azabicyclo[3.2.1]octan-3-ol (556 mg), phthalimide (321 mg) and polymer bound triphenylphosphine (821 mg) were combined in tetrahydrofuran (10 ml). Diethylazodicaboxylate (330 μl) was added and the mixture was stirred gently overnight. Additional phosphine (0.5 g) and diethylazodicaboxylate (200 μl) were added and the mixture was stirred for an additional 5 days. The reaction mixture was diluted with ethyl acetate and filtered; the residue was washed with ethyl acetate and methanol. The filtrate was evaporated, and chromatographed eluting with 9:1 ethyl acetate:methanol. RPHPLC of the product (gradient ammonium acetate 1% aqueous:acetonitrile (25% acetonitrile to 100% acetonitrile)) gave the subtitle compound (90 mg).

¹H NMR (399.978 MHz, CDCl₃) δ 1.47-1.39 (m, 2H), 1.78 (d, J=7.7 Hz, 2H), 2.14-2.02 (m, 2H), 2.64 (t, J=11.8 Hz, 2H), 3.36-3.25 (m, 2H), 3.92-3.81 (m, 2H), 4.56 (septet, J=6.1 Hz, 1H), 7.41-7.32 (m, 2H), 7.59-7.55 (m, 1H), 7.74-7.69 (m, 2H), 7.86-7.82 (m, 2H).

Step iii: Exo-8-[(3,4-dichlorophenyl)methyl]-8-azabicyclo[3.2.1]octan-3-amine

Exo-2-[8-[(3,4-dichlorophenyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]-1H-isoindole-1,3(2H)-dione (90 mg) was dissolved in ethanol (6 ml) containing dichloromethane (3 ml); hydrazine hydrate (0.2 ml) was added and the resulting solution was stirred at room temperature for 26 hours. The suspension was filtered and the filtrate was evaporated to give the subtitle compound (55 mg).

¹H NMR (399.978 MHz, CDCl₃) δ 1.51-1.43 (m, 2H), 1.59 (q, J=4.9 Hz, 2H), 1.75-1.67 (m, 2H), 2.00-1.94 (m, 2H), 3.02-2.92 (m, 1H), 3.18-3.12 (m, 2H), 3.50 (s, 3H), 7.21 (d, J=8.2 Hz, 1H), 7.37 (d, J=8.2 Hz, 1H), 7.50 (s, 1H).

Step iv: Exo-N-[8-[(3,4-dichlorophenyl)methyl]-8-azabicyclo[3.2.1]oct-3-yl]-3-(2-pyridinyl)-1,2,4-oxadiazole-5-propanamide

Prepared following the method of Example 370 step (iii) but without salt formation to give the title compound (15 mg). m.p. 177.5-178° C.

¹H NMR (299.946 MHz, DMSO): δ 1.63-1.43 (m, 6H), 1.99-1.90 (m, 2H), 2.64 (t, J=7.1 Hz, 2H), 3.11-3.06 (m, 2H), 3.18 (t, J=6.2 Hz, 2H), 3.49 (s, 2H), 3.97-3.83 (m, 1H), 7.32 (dd, J=8.3, 1.9 Hz, 1H), 7.62-7.56 (m, 3H), 7.87 (d, J=8.1 Hz, 1H), 8.06-7.97 (m, 2H), 8.75 (dt, J=3.7, 0.8 Hz, 1H).

Example 374 (R) N-[1-[1-(4-bromophenyl)ethyl]-4-piperidinyl]-3-(2-pyridinyl)-1,2,4-oxadiazole-5-propanamide

Step i: (R)-1-[1-(4-Bromophenyl)ethyl]-4-piperidinone

(R)-(4-Bromophenyl)ethylamine (1.01 g) and potassium carbonate (1.45 g) were dissolved in a mixture of ethanol (13 ml) and water (6 ml) and then heated to a vigorous reflux. A solution of 4-hydroxy-4-methoxy-1,1-dimethyl-piperidinium iodide (J. Chem. Soc. Perkin Trans. 2, (1984) 1647) (1.47 g) in warm water (6 ml) was added dropwise over 40 minutes; reflux was maintained for a further 12 hours, then the reaction was allowed to cool to room temperature. The mixture was evaporated and ethyl acetate and water were added and the phases were separated. The aqueous phase was extracted twice with ethyl acetate, the organic layer was washed with brine, dried, filtered and evaporated. Chromatography of the residue eluting with iso-hexane:ethyl acetate (3:2) gave the subtitle compound (804 mg).

¹H NMR (399.978 MHz, CDCl₃) δ 2.66-2.80 (m, 4H), 1.38 (d, J=6.9 Hz, 3H), 2.42 (t, J=6.2 Hz, 4H), 3.58 (q, J=6.7 Hz, 1H), 7.24 (d, J=8.5 Hz, 2H), 7.46 (d, J=9.0 Hz, 4H).

Step ii: (R)-1-[1-(4-Bromophenyl)ethyl]-4-piperidinamine

Prepared following the general method of Example 370 step (i) (R)-1-[1-(4-bromophenyl)ethyl]-4-piperidinone (420 mg) ammonium acetate (0.80 g) and sodium cyanoborohydride (120 mg) to give the subtitle compound (449 mg).

¹H NMR (399.978 MHz, CDCl₃) δ 1.33 (d, J=6.9 Hz, 3H), 1.43-1.26 (m, 2H), 1.73 (d, J=12.3 Hz, 1H), 1.81 (d, J=12.6 Hz, 1H), 2.03-1.90 (m, 2H), 2.60 (tt, J=10.6, 5.1 Hz, 1H), 2.71 (d, J=13.6 Hz, 1H), 2.94 (d, J=11.3 Hz, 1H), 3.37 (q, J=6.7 Hz, 1H), 7.18 (d, J=8.5 Hz, 2H), 7.43 (d, J=8.2 Hz, 2H)

Step iii: (R) N-[1-[1-(4-bromophenyl)ethyl]-4-piperidinyl]-3-(2-pyridinyl)-1,2,4-oxadiazole-5-propanamide

Prepared following a method as hereinbefore described using (R)-1-[1-(4-bromophenyl)ethyl]-4-piperidinamine (449 mg), 3-(2-pyridinyl)-1,2,4-oxadiazole-5-propanoic acid (0.31 g), 1-hydroxybenzotriazole (0.20 g), 4-(N,N-dimethylamino)-pyridine (0.13 g) and 1-ethyl-3-[3-(dimethylamino)-propyl]carbodiimide hydrochloride (0.30 g) to give the title compound (40 mg). m.p. 153-155° C.

¹H NMR (399.98 MHz, DMSO) δ 1.23 (d, J=6.7 Hz, 3H), 1.40-1.26 (m, 2H), 1.66-1.61 (m, 1H), 1.73-1.67 (m, 1H), 1.97-1.86 (m, 2H), 2.64-2.59 (m, 1H), 2.66 (t, J=7.2 Hz, 2H), 2.84-2.79 (m, 1H), 3.18 (t, J=7.2 Hz, 2H), 3.42 (q, J=6.4 Hz, 1H), 3.48-3.39 (m, 1H), 7.25 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.5 Hz, 2H), 7.59 (ddd, J=6.7, 4.6, 2.1 Hz, 1H), 7.91 (d, J=7.4 Hz, 1H), 8.04-7.99 (m, 2H), 8.75 (dt, J=4.4, 1.4 Hz, 1H).

Example 375 (S) N-[1-[1-(4-bromophenyl)ethyl]-4-piperidinyl]-3-(2-pyridinyl)-1,2,4-oxadiazole-5-propanamide

Prepared following an analogous series of steps to example 374 but using (S)-(4-bromophenyl)ethylamine bromophenyl)ethylamine to give the title compound. m.p. 141.5-143° C. α_(D −)29.55° (c=0.13, methanol, 21° C.)

¹H NMR (299.946 MHz, DMSO) δ 1.23 (d, J=6.7 Hz, 3H), 1.26-1.41 (m, 2H), 1.64 (t, J=8.1 Hz, 2H), 1.92 (q, J=11.2 Hz, 2H), 2.58-2.67 (m, 1H), 2.67 (t, J=7.2 Hz, 2H), 2.78-2.85 (m, 1H), 3.18 (t, J=7.1 Hz, 2H), 3.37-3.46 (m, 1H), 3.42 (q, J=6.7 Hz, 1H), 7.25 (d, J=6.7 Hz, 2H), 7.49 (d, J=8.5 Hz, 2H), 7.57-7.62 (m, 1H), 7.91 (d, J=7.7 Hz, 1H), 7.98-8.05 (m, 2H), 8.75 (d, J=7.5 Hz, 1H).

Example 385 1-[3,4-Dichlorobenzyl]-N-[3-(3-pyridinyl)propyl]-4-piperidinamine

The title compound was prepared from 1-(3,4-dichlorobenzyl)piperidine-4-amine (free base 187 mg), 3-(3-pyridinyl)propanal (125 mg), sodium triacetoxyborohydride (70 mg), and 0.02 ml acetic acid, stirred together for 2 hrs in dichloromethane (10 ml). Water was added, the mixture neutralised with sodium bicarbonate and the organic phase separated, dried and chromatographed on silica with ethyl acetate/methanol (9:1) as eluant, to give the title compound (70 mg) as a colourless oil.

MS [M+H]⁺ (ES+) 378 ¹H NMR: (CDCl₃) δ 1.36-1.40 (2H, m), 1.75-1.85 (4H m), 2.0 (2H, t), 2.1-2.2 (2H, m), 2.4-2.45 (1H m), 2.6-2.7 (3H, m), 2.75-2.79 (2H, m), 3.4 (2H, s), 7.1-7.54 (5H, d), 8.44 (2H, m).

Example 386 2-[(1,1′-Biphenyl)-4-yloxy]-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]acetamide

MS [M+H]⁺ (ES+) 469 ¹H NMR: (CDCl₃) δ 1.46-1.50 (2H, m), 1.7-1.8 (2H, m), 2.0-2.1 (2H, m), 2.5-2.6 (2H, m), 3.45 (2H, s), 3.65-3.7 (1H, m), 4.5 (2H, s), 7.25-7.3 (2H, m), 7.27-7.63 (9H, m), 8.0 (1H, d).

Example 387 N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-4-phenyl-3-butenamide

MS [M+H]⁺ (ES+) 403 ¹H NMR: (CDCl₃) δ 1.46-1.40 (2H, m), 1.85-1.95 (2H, d), 2.05-2.15 (2H, t), 2.75-2.79 (2H, d), 3.1 (2H, d), 3.4 (2H, s), 3.85-3.95 (1H, m), 5.45 (1H, m), 6.3 (1H, m), 6.5 (1H, d), 7.07-7.43 (8H, m).

Example 388 N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-3-(3-methoxyphenyl)-2-propenamide.

MS [M+H]⁺ (ES+) 419 ¹H NMR: (CDCl₃) δ 1.46-1.50 (2H, m), 2.0 (2H, m), 2.15-2.25 (2H, m), 2.75-2.85 (2H, m), 3.4 (2H, s), 3.8 (3H, s), 3.94-4.05 (1H, m), 5.5 (1H, d), 6.35-6.4 (1H, d), 6.9-7.5 (7H, m), 7.6 (1H, d).

Example 389 N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-3-(4-iodophenoxy)propanamide.

MS [M+H]⁺ (ES+) 533 ¹H NMR: (CDCl₃) δ 1.46-1.50 (2H, m), 1.9 (2H, d), 2.1-2.2 (2H, t), 2.6 (2H, m), 2.75-2.85 (2H, d), 3.4 (2H, d), 3.8-3.9 (1H, m), 4.20 (2H, m), 6.65-6.7 (2H m), 7.1-7.2 (1H, d), 7.35-7.45 (2H, m), 7.54-7.6 (2H, m).

Example 390 N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-N′-(4-methoxyphenyl)succinamide

MS [M+H]⁺ (ES+) 464 ¹H NMR: (CDCl₃) δ 1.4 (2H, m), 1.6-1.65 (2H, m), 2.05 (2H, m), 2.45 (2H, m), 2.65-275 (2H, m), 3.0 (2H, m) 3.45 (2H, s), 3.5 (1H, m), 3.7 (3H, s), 5.9 (1H, m), 6.85 (2H, d), 7.3-7.6 (4H, m), 7.7 (1H, d), 9.7 (1H, s).

Example 391 N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-[(5-phenyl-2-pyrimidinyl)oxy] acetamide

MS [M+H]⁺ (ES+) 471 ¹H NMR: (CDCl₃) δ 1.46-1.50 (2H, m), 1.9-2.0 (2H, m), 2.0-2.1 (2H, m), 2.75-2.85 (2H, m), 3.4 (2H, s), 3.9-4.0 (1H, m), 4.92 (2H, s), 6.53 (1H, d), 7.1-7.6 (7H, m), 7.7 (1H, s), 8.76 (2H, s).

Example 392 N-[1-(4-iodobenzyl)-4-piperidinyl]-2-(5-phenyl-2-pyrimidinyl)thio]acetamide

MS [M+H]⁺ (ES+) 545 ¹H NMR: (CDCl₃) δ 1.46-1.50 (2H, m), 1.8 (2H, m), 2.1-2.2 (2H, t), 2.65 (2H, m), 3.4 (2H, s), 3.9 (3H, m), 6.8 (1h, d), 7.0 (2H, m), 7.5-7.7 (7H, m), 8.8 (2H, d).

Example 393 N-[1-(3,4-dichlorobenzy)-4-piperidinyl]-2-[(2-pyrimidinyl)thio]acetamide

MS [M+H]⁺ (ES+) 412 ¹H NMR: (CDCl₃) δ 1.46-1.50 (2H, m), 1.8 (2H, m), 2.1 (2H, m), 2.65 (2H, m), 3.4 (2H, s), 3.8 (3H, m), 6.90 (1H m), 7.05-7.2 (4H, m), 8.58 (2H, d).

Example 394 2-[(5-Bromo-2-pyrimidinyl)thio]-N-[1-(3,4-dichlorobenzy)-4-piperidinyl]acetamide

MS [M+H]⁺ (ES+) 491 ¹H NMR: (CDCl₃) δ 1.46-1.50 (2H, m), 1.8 (2H, m), 2.15 (2H, m), 2.6 (2H, m), 3.4 (2H, s), 3.8 (3H, m), 6.6 (1H, d), 7.1 (1H m), 7.3-7.4 (2H, m) 8.58 (2H, d).

Example 395 N-[1-(3,4-difluororobenzyl)-4-piperidinyl]-2-(4-pyridinylthio)acetamide

MS [M+H]⁺ (ES+) 378 ¹H NMR: (CDCl₃) δ 1.36-1.40 (2H, m), 1.8 (2H, m), 2.05 (2H m), 2.65 (2H, m), 3.4 (2H, m), 3.67 (2H, s), 3.8 (1H, m), 6.5 (1H, m), 6.9-7.24 (4H, m) 8.48 (2H, d).

Example 396 N-[1-(3,4-dichlorobenzy)-4-piperidinyl]-3-(5-phenyl-1H-pyrrol-2-yl)propanamide

MS [M+H]⁺ (ES+) 454 ¹H NMR: (CDCl₃) δ 1.36-1.40 (2H, m), 1.87 (2H, m), 2.05 (2H m), 2.5 (2H, m), 2.65 (2H, m), 2.96 (2H, m), 3.4 (2H, s), 3.8 (1H, m), 5.35 (1H, d), 5.95-6.0 (1H, m) 6.38 (1H, m), 7.1-7.5 (8H, m), 9.5 (1H m).

Example 397 N-[1-(3,4-dichlorobenzy)-4-piperidinyl]-N′-(5-phenyl-2-pyrimidinyl)-1,2-ethandiamine

The title compound (20 mg) was prepared by heating at reflux N¹-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-1,2-ethanediamine (100 mg) and 2-chloro-5-phenypyrimidine (100 mg) and Hunigs' base (100 mg) in toluene for 8 hours. The mixture was purified by chromatography on silica, with ethyl acetate methanol (9:1) as eluant to give the title compound as a yellow oil. MS [M+h]⁺ (ES+) 456/8 ¹H NMR: (CDCl₃) δ 1.51 (2H, m), 1.75 (2H, m), 2.15 (2H, td), 2.9 (2H, m), 3.05 (1H, m), 3.15 (2H, m), 3.44 (2H, m), 3.8 (2H, m), 6.65 (1H, m), 7.0-7.4 (8H, m), 8.5 (2H, m).

Example 398 N-[5-bromo-2-pyrimidinyl]-N′-[1-(3,4-dichlorobenzy)-4-piperidinyl]-1,2-ethandiamine

Prepared by the method of Example 397 amine (200 mg), 2-chloro-5-bromopyrimidine (130 mg), Hunigs' base (200 mg) to give the title compound (20 mg). MS [M+H]⁺ (ES+) 458/60 ¹H NMR: (CDCl₃) δ 1.4 (2H, m), 1.75 (2H, m), 2.05 (2H, td), 2.85 (2H, m), 3.0 (1H, m), 3.15 (2H, m), 3.44 (2H, m), 3.75 (2H, m), 6.8 (1H, m), 7.0-7.4 (3H, m), 8.25 (2H, m).

Example 399 2-[(2-Chloro-4-pyrimidinyl)amino]-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]acetamide

MS [M+H]⁺ (ES+) 430/32 ¹H NMR: (CDCl₃) δ 1.40-1.45 (2H, m), 1.97 (2H, m), 2.15 (2H m), 2.75 (2H, d), 3.4 (2H, s), 3.8 (1H, m), 4.05 (2H, d), 5.75 (1H, d), 5.84 (1H m), 6.38 (1H, d), 7.1-7.15 (1H d), 7.36-7.42 (2H m), 8.0 (1H d).

Example 401 2-[(5-Bromo-2-pyrimidinyl)oxy]-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-acetamide

MS [M+H]⁺ (ES+) 475 ¹H NMR: (CDCl₃) δ 1.46-1.50 (2H, m), 1.87 (2H, m), 2.15 (2H, m), 2.75 (2H, m), 3.4 (2H, s), 3.9 (1H, m) 4.8 (2H, s), 6.38 (1H, d), 7.1-7.15 (1H m), 7.4 (2H, m), 8.6 (2H, s).

Example 402 N-[1-(3,4-dichlor benzy)-4-piperidinyl]-2-(1,3-di x -1,3-dihydro-2H-is indol-2-yl)acetamide

MS [M+H]⁺ (ES+) 446 ¹H NMR: (CDCl₃) δ 1.46-1.50 (2H, m), 1.87 (2H, m), 2.15 (2H m), 2.75 (2H, m), 3.4 (2H, s), 3.8 (1H, m), 4.3 (2H s), 5.65 (1H, m), 7.1-7.36 (3H, m) 7.38-7.78 (2H, m), 7.87-7.95 (2H, m).

Example 403 N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-N-[2-(2-pyridinylthio)ethylamine, dihydrochloride

¹H NMR: (CDCl₃) (of the free base): δ 1.4 (2H, m) 1.85 (2H, m), 2.05 (2H, m) 2.55 (2H, td), 2.8 (2H, m), 3.0 (1H, m), 3.3 (2H, m), 3.42 (2H, s), 6.9-7.5 (4H, m), 8.5 (2H, m).

Example 404 N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-3-(phenylthio)propanamide

MS [M+h]⁺ (ES+) 423 ¹H NMR: (CDCl₃) δ 1.36-1.40 (2H, m), 1.87 (2H, m), 2.15 (2H m), 2.45 (2H, m), 2.76 (2H, m), 3.2 (2H, m), 3.4 (2H, s), 3.8 (1H, m), 5.4 (1H, d), 7.1-7.5 (8H m).

Example 405 N′-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-[4-(trifluoromethoxy)phenoxy]acetohydrazide

The title compound was prepared from 3,4-dichlorobenzyl-4-piperidone (J. Med. Chem, 1999, 42, 3629; 100 mg), 2-[4(trifluoromethoxy)phenoxy]acetohydrazide (100 mg), sodium triacetoxyborohydride (100 mg), and 0.02 ml acetic acid, stirred together for 2 hours in dichloromethane by the method of Example 369 step ii. MS [M+H]⁺ (ES+) 492 ¹H NMR: (CDCl₃) δ 1.4-1.6 (3H, m) 1.7 (2H, m), 2.0 (2H, m) 2.7-2.9 (2H, m), 3.4 (2H, m), 4.4 (3H, m), 5.3 (1H, s) 6.9 (2H, m), 7.2-7.5 (4H, m), 7.8 (1H, d).

Example 406 N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-N-[3-[3-(2-pyridinyl)-1,2,4-oxadiazo-5-yl]propyl]amine

The title compound (29 mg) was prepared from 3,4-dichlorobenzylpiperidine-4-amine (100 mg free base), 2-[5-(3-bromopropyl)-1,2,4-oxadiazol-3-yl]pyridine (100 mg), potassium carbonate (100 mg) in dimethyl formamide (1 ml) were heated together in the microwave for 30 secs, water was added and the product extracted into dichloromethane and chromatographed on silica with ethyl acetate/methanol (9:1) as eluant. MS [M+H]⁺ (ES+) 446 ¹H NMR: (CDCl₃) δ 1.4 (2H, m) 1.7-1.9 (4H, m), 2.0-2.1 (4H, m) 2.46 (1H, m), 2.75 (2H, m), 3.1 (2H, t), 3.4 (2H, s), 7.15-7.45 (4H, m), 7.85 (1H, t) 8.1 (1H, d) 8.8 (1H, d).

Example 407 N-[2-[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino]ethyl]-3-(methylsulphonyl)benzamide

Prepared from N-(2-aminoethyl)-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2,2,2-trifluoroacetamide (100 mg), 3-methylsulphonylbenzoic acid (50 mg) and carbonyldiimidazole (40 mg). The product obtained was stirred together with sodium hydroxide (40 mg) in 50:50 methanol/water for 12 hrs, extracted into dichloromethane and purified by chromatography on silica with ethyl acetate/methanol (9:1) as eluant, to give the title compound (25 mg). MS [M+H]⁺ (ES+) 485 ¹H NMR: (CDCl₃) δ 1.4 (2H, m) 1.9 (2H, m), 2.0-2.1 (1H, m) 2.6 (1H, m), 2.8 (2H, m), 2.95 (2H, m) 3.1 (3H, m) 3.4 (2H, s), 3.6 (2H, m), 7.15 (2H, m), 7.4 (2H, m), 7.65 (1H, t) 8.1 (2H d) 8.4 (1H, d).

Example 408 3-[5-(4-chlorophenyl-4H-1,2,4-triazol-3-yl]-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl])propanamide

MS [M+H]⁺ (ES+) 493 ¹H NMR: (CDCl₃) δ 1.6 (2H, m), 1.87 (2H, m), 2.25 (2H m), 2.65 (2H, m), 2.86 (96 (2H, m), 3.14 (2H, m), 3.5 (2H, s), 3.85 (1H, m), 6.0 (1H, m) 7.23 (1H, m), 7.4 (3H m), 7.45 (1H m), 8.0 (2H m).

Example 409 N-[1-(3,4-dichl r benzyl)-4-piperidinyl]-3-(2-pyridinyl)propanamide

MS [M+H]⁺ (ES+) 394 ¹H NMR: (CDCl₃) δ 1.46 (2H, m), 1.8 (2H, m), 2.15 (2H m), 2.75 (4H, m), 3.3 (2H m), 3.45 (2H, s), 3.8 (1H, m), 6.05 (1H, m), 7.1 (2H, m) 7.38 (1H, m), 7.45 (1H m), 8.65 (2H m)

Example 410 N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-4-(4-(methylsulphonyl)phenyl-4-oxobutanamide

MS [M+H]⁺ (ES+) 497 ¹H NMR: (CDCl₃) δ 1.4-1.5 (2H, m), 1.9 (2H, m), 2.15 (2H m), 2.65 (2H, m), 2.78 (2H m), 3.1 (3H s), 3.35 (2H m), 3.4 (2H, s), 3.8 (1H, m), 5.55 (1H, m), 7.16 (1H, m) 7.38 (2H, m), 8.05 (2H m), 8.2 (2H m).

Example 411 N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-N′-[4-(methylsulphonyl) benzylamine

MS [M+H]⁺ (ES+) 427 ¹H NMR: (CDCl₃) δ 1.4 (2H, m), 1.8-1.9 (2H, m), 2.0 (2H, m), 2.5 (2H, td), 2.8 (2H, m), 3.0 (2H, s), 3.4 (2H, s), 3.94 (2H, s), 7.15 (1H, m), 7.4 (2H, m), 7.55 (2H, d) 7.9 (2H, d).

Example 412 N-[1-(3,4-dichl r benzyl)-4-piperidinyl]-N′-[(2-pyridinyl) succinamide

MS [M+H]⁺ (ES+) 435 ¹H NMR: (CDCl₃) δ 1.6 (2H, m), 1.87 (2H, m), 2.05 (2H m), 2.65 (2H, m), 2.76 (4H m), 3.4 (2H, s), 3.8 (1H, m), 5.65 (1H, m), 7.0 (1H, m), 7.1 (1H, m), 7.38 (2H, d), 7.7 (1H m), 8.2 (1H m), 8.27 (1H m), 8.65 (1H m).

Example 413 N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-(4-phenyl-1,3-thiazol-2-yl))acetamide

MS [M+H]⁺ (ES+) 461 ¹H NMR: (CDCl₃) δ 1.50 (2H, m), 1.87 (2H, m), 2.15 (2H m), 2.65 (2H, m), 3.4 (2H, s), 3.85 (1H m), 4.0 (2H, s), 7.15 (1H, d) 7.3-7.5 (6H, m), 7.9 (2H d).

Example 414 N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-(2-phenyl-1,3-thiazol-4-yl))acetamide

MS [M+H]⁺ (ES+) 461 ¹H NMR: (CDCl₃): δ 1.45 (2H, m), 1.90 (2H, m), 2.15 (2H m), 2.65 (2H, m), 3.25 (2H, s), 3.7 (2H, s), 3.85 (1H, m), 7.15 (2H, m) 7.4 (2H, d), 7.5 (3H m), 8.0 (2H m).

Example 415 N-[1-(3,4-difluorobenzyl)-4-piperidinyl]-3-(3-2-pyridinyl-1,2,4-oxadiazol-5-yl]propanamide

MS [M+H]⁺ (ES+) 428 ¹H NMR: (CDCl₃) δ 1.36-1.45 (2H, m), 2.0 (2H, m), 2.1-2.2 (2H, t), 2.7-2.85 (4H, m), 3.34 (2H, d), 3.4 (2H, d), 3.8 (1H, m), 5.6 (1H, d), 7.0-7.2 (3H m), 7.4 (1H m), 7.8 (1H, m) 8.1 (1H, d), 8.8 (1H, d)

Example 416 N-trifluoroacetyl-N-[2-[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino]ethyl]-3-methoxybenzamide

a) tert-butyl 2-{[1-(3,4-dichlorobenzyl)-4-piperidinyl]amino}ethylcarbamate

The sub-title compound (800 mg) was prepared from 3,4-dichlorobenzyl-4-piperidone (1.3 g) tert-butyl 2-aminoethylcarbamate (0.8 g), sodium triacetoxyborohydride (100 mg), and 0.02 ml acetic acid, stirred together for 2 hrs in dichloromethane. The sub-titled compound was isolated by standard procedures. MS [M+H]⁺ (ES+) 402

b) N-(2-aminoethyl)-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2,2,2-trifluoroacetamide

A mixture of the above amine (800 mg), and triethylamine (0.5 ml) in dichloromethane (50 ml), treated with trifluoroacetic anhydride (420 mg) over 30 mins, evaporated to dryness and dichloromethane (20 ml) and trifluoroacetic acid (2 ml) added, stirred for 3 hrs, then neutralised with aqueous sodium bicarbonate, the organic phase separated, dried and evaporated to give the title compound (250 mg) as a yellow oil. MS [M+H]⁺ (ES+) 496/8

c) N-trifluoroacetyl-N-[2-[1-(3,4-dichlor benzyl)-4-piperidinyl]amin]ethyl]-3-methoxybenzamide

The title compound (30 mg) was prepared from the product above (40 mg) 3-methoxybenzoyl chloride (20 mg) and triethylamine (50 mg) using one of the methods described above. MS [M+H]⁺ (ES+) 580 ¹H NMR: (CDCl₃) δ 0.9 (6H, m) 1.2-1.4 (6H, m), 1.6-1.85 (4H, m) 2.8 (1H, m), 3.3 (4H, m), 3.6-3.8 (5H, m), 3.8 (2H, s), 7.0 (1H, m), 7.1 (1H, m), 7.35-7.45 (3H, m), 8.25 (1H, t).

Further compounds of formula (I), all according to formula (Ic), are shown in the table below.

(Ic)

Example R¹ (Q)_(m) (CR²R³)_(n) T¹ R* Z R⁶ 380 4-Cl—C₆H₄ O CH₂ C(O) H CH₂C(O)NH 2-Cl-5-CH₃—C₆H₃ 381 4-Cl—C₆H₄ O CH₂ C(O) H (CH₂)₃ C₆H₅ 382 3-(pyridin-2-yl)- O CH₂ C(O) H allyl C₆H₅ 1,2,4-oxadiazol-5-yl 383 2-(cyclopropyl-NH)- m = 0 n = 0 — CH₃ CH₂ 3,4-Cl₂—C₆H₃ pyrimidin-4-yl 384 2-(pyridin-3-yl)- m = 0 n = 0 — CH₃ CH₂ 3,4-Cl₂—C₆H₃ pyrimidin-4-yl 400 pyrimidin-2-yl S CH₂ C(O) H C(O) 3,4-Cl₂—C₆H₃ Pharmacological Analysis Calcium flux [Ca²⁺]_(i) assay a) Human eosinophils

Human eosinophils were isolated from EDTA anticoagulated peripheral blood as previously described (Hansel et al., J. Immunol. Methods, 1991, 145, 105-110). The cells were resuspended (5×10⁶ ml⁻¹) and loaded with 5 μM FLUO-3/AM+Pluronic F127 2.2 μl/ml (Molecular Probes) in low potassium solution (LKS; NaCl 118 mM, MgSO₄ 0.8 mM, glucose 5.5 mM, Na₂CO₃ 8.5 mM, KCl 5 mM, HEPES 20 mM, CaCl₂ 1.8 mM, BSA 0.1%, pH 7.4) for one hour at room temperature. After loading, cells were centrifuged at 200 g for 5 min and resuspended in LKS at 2.5×10⁶ ml⁻¹. The cells were then transferred to 96 well FLIPr plates (Poly-D-Lysine plates from Becton Dickinson pre-incubated with 5 μM fibronectin for two hours) at 100 ml/well. The plate was centrifuged at 200 g for 5 min and the cells were washed twice with LKS (200 μl; room temperature).

A compound of the Examples was pre-dissolved in dimethylsulphoxide and added to a final concentration of 0.1% (v/v) dimethylsulphoxide. Assays were initiated by the addition of an A₅₀ concentration of eotaxin and the transient increase in fluo-3 fluorescence (1_(Ex)=490 nm and 1_(Em)=520 nm) monitored using a FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices, Sunnyvale, U.S.A.).

b) Human monocytes

Human monocytes were isolated from EDTA anticoagulated peripheral blood as previously described (Cunoosamy & Holbrook, J. Leukocyte Biology, 1998, S2, 13). Cells were resuspended (5×10⁶ ml⁻¹) in LKS and loaded with 5 μM FLUO-3/AM+Pluronic F127 2.2 μl/ml (Molecular Probes) for one hour at room temperature. After loading, cells were centrifuged at 200 g for 5 min and resuspended in LKS at 0.5×10⁶ ml⁻¹. The cells were then transferred to 96 well FLIPr plates (Costar). To each well 100 μl of cells were added at a concentration of 0.5×10⁶ ml⁻¹. The plates were centrifuged (200 g; 5 mins; room temperature) to allow the cells to adhere. After centrifugation the cells were washed twice with LKS (200 μl; room temperature).

A compound of the Examples was pre-dissolved in dimethylsulphoxide and added to a final concentration of 0.1% (v/v) dimethylsulphoxide. Assays were initiated by the addition of an A₅₀ concentration of MIP-1α and the transient increase in fluo-3 fluorescence (1_(Ex)=490 nm and 1_(Em)=520 nm) monitored using a FLIPR (Fluorometric Imaging Plate Reader, Molecular Devices, Sunnyvale, U.S.A.).

The compounds of the Examples were found to be antagonists of the eotaxin mediated [Ca²⁺]_(i) in human eosinophils and/or antagonists of the MIP-1α mediated [Ca²⁺]_(i) in human monocytes.

Human eosinophil chemotaxis

Human eosinophils were isolated from EDTA anticoagulated peripheral blood as previously described (Hansel et al., J. Immunol. Methods, 1991, 145, 105-110). The cells were resuspended at 10×10⁶ ml⁻¹ in RPMI containing 200 IU/ml penicillin, 200 μg/ml streptomycin sulphate and supplemented with 10% HIFCS, at room temperature.

Eosinophils (700 μl) were pre-incubated for 15 mins at 37° C. with 7 μl of either vehicle or compound (100× required final concentration in 10% dimethylsulphoxide). The chemotaxis plate (Chemo Tx, 3 μm pore, Neuroprobe) was loaded by adding 28 μl of a concentration of eotaxin (0.1 to 100 nM) containing a concentration of a compound according to the Examples or solvent to the lower wells of the chemotaxis plate. The filter was then placed over the wells and 25 μl of eosinophil suspension were added to the top of the filter. The plate was incubated for 1 hr at 37° C. in a humidified incubator with a 95% air/5% CO₂ atmosphere to allow chemotaxis.

The medium, containing cells that had not migrated, was carefully aspirated from above the filter and discarded. The filter was washed once with phosphate buffered saline (PBS) containing 5 mM EDTA to remove any adherent cells. Cells that had migrated through the filter were pelleted by centrifugation (300×g for 5 mins at room temperature) and the filter removed and the supernatant transferred to each well of a 96-well plate (Costar). The pelleted cells were lysed by the addition of 28 μl of PBS containing 0.5% Triton ×100 followed by two cycles of freeze/thawing. The cell lysate was then added to the supernatant. The number of eosinophils migrating was quantified according to the method of Strath et al., J. Immunol. Methods, 1985, 83, 209 by measuring eosinophil peroxidase activity in the supernatant.

Certain compounds of the Examples were found to be antagonists of the eotaxin mediated human eosinophil chemotaxis. 

1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, or solvate thereof, or a solvate of a salt thereof:

wherein Z is CR⁴R⁵, wherein R⁴ and R⁵ are CH₂; R¹ represents a 3- to 14-membered saturated or unsaturated ring system which comprises up to two ring carbon atoms that form carbonyl groups and which further comprises up to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulphur, wherein the ring system is optionally substituted by one or more substituents independently selected from: halogen, cyano, nitro, oxo, hydroxyl, C₁-C₈ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁₋₆ alkoxy(C₁-C₆ alkyl), C₃-C₇ cycloalkyl(C₁-C₆ alkyl), C₁-C₆ alkylthio(C₁-C₆ alkyl), C₁-C₆ alkylcarbonyloxy(C₁-C₆ alkyl), C₁-C₆ alkylS(O)₂(C₁-C₆ alkyl), aryl(C₁-C₆ alkyl), heterocycly(C₁-C₆ alkyl), arylS(O)₂(C₁-C₆ alkyl), heterocyclylS(O)₂(C₁-C₆ alkyl), aryl(C₁-C₆ alkyl)S(O)₂, heterocyclyl(C₁-C₆ alkyl(S(O)₂, C₂-C₆ alkenyl, C₁-C₆ alkoxy, carboxy-substituted C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ hydroxyalkoxy, C₁-C₆ alkylcarboxy-substituted C₁-C₆ alkoxy, aryloxy, heterocyclyloxy, C₁-C₆ alkylthio, C₃-C₇ cycloalkyl(C₁-C₆ alkylthio), C₃-C₆ alkynylthio, C₁-C₆ alkylcarbonylamino, C₁-C₆ haloalkylcarbonylamino, SO₃H, —NR⁷R⁸, —C(O)NR²³R²⁴, S(O)₂NR¹⁸R¹⁹, S(O)₂R²⁰, R²⁵C(O), carboxyl, C₁-C₆ alkoxycarbonyl, aryl and heterocyclyl; wherein the foregoing aryl and heterocyclyl moieties are optionally substituted by one or more of halogen, oxo, hydroxy, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl(C₁-C₆ alkyl), C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, S(O)₂(C₁-C₆ alkyl), C(O)NH₂, carboxy or C₁-C₆ alkoxycarbonyl; m is 0; n is 2; each R² and R³ independently represents a hydrogen atom or a C₁-C₄ alkyl group, or (CR²R³)_(n) represents C₃-C₇ cycloalkyl optionally substituted by C₁-C₄ alkyl; T represents a group C(O)NR¹⁰, wherin R¹⁰ is H; X¹, X², X³ and X⁴ are, independently, CH₂; R⁴ and R⁵ each independently represent a hydrogen atom or a C₁-C₄ alkyl group; R⁶ is phenyl, optionally substituted by one or more of: halogen, cyano, nitro, oxo, hydroxyl, C₁-C₈ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁₋₆ alkoxy(C₁-C₆ alkyl), C₃-C₇ cycloalkyl(C₁-C₆ alkyl), C₁-C₆ alkylthio(C₁-C₆ alkyl), C₁-C₆ alkylcarbonyloxy(C₁-C₆ alkyl), C₁-C₆ alkylS(O)₂(C₁-C₆ alkyl), aryl(C₁-C₆ alkyl), heterocyclyl(C₁-C₆ alkyl), arylS(O)₂(C₁-C₆ alkyl), heterocyclylS(O)₂(C₁-C₆ alkyl), aryl(C₁-C₆ alkyl)S(O)₂, heterocyclyl(C₁-C₆ alkyl)S(O)₂, C₂-C₆ alkenyl, C₁-C₆ alkoxy, carboxy-substituted C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ hydroxyalkoxy, C₁-C₆ alkylcarboxy-substituted C₁-C₆ alkoxy, aryloxy, heterocyclyloxy, C₁-C₆ alkylthio, C₃-C₇ cycloalkyl(C₁-C₆ alkylthio), C₃-C₆ alkynylthio, C₁-C₆ alkylcarbonylamino, C₁-C₆ haloalkylcarbonylamino, SO₃H, —NR¹⁶R¹⁷, —C(O)NR²¹R²², S(O)₂NR¹³R¹⁴, S(O)₂R¹⁵, R²⁶C(O), carboxyl, C₁-C₆ alkoxycarbonyl, aryl and heterocyclyl; wherein the foregoing aryl and heterocyclyl moieties are optionally substituted by one or more of halogen, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl(C₁-C₆ alkyl), C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, S(O)₂(C₁-C₆ alkyl), C(O)NH₂, carboxy or C₁-C₆ alkoxycarbonyl; R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²¹, R²², R²³ and R²⁴ are, independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl) or phenyl(C₁-C₆ alkyl); and, R¹⁵ and R²⁰ are, independently, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₃-C₆ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl) or C₁-C₆ alkyl optionally substituted by phenyl; R²⁵ and R²⁶ are, independently, C₁-C₆ alkyl or phenyl (optionally substituted by one or more of halogen, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl(C₁-C₆ alkyl), C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, S(O)₂(C₁-C₆ alkyl), C(O)NH₂, carboxy or C₁-C₆ alkoxycarbonyl).
 2. A compound as defined in any one of Examples 1 to
 416. 3. A process for the preparation of a compound of formula (I) as defined in claim 1 which comprises: (a) when T is C(O)NR¹⁰, reacting a compound of general formula

 wherein R¹, R², R³, Q, m and n are as defined in formula (I), with a compound of formula (III)

 wherein X¹, X², X³, X⁴, Z, R⁶ and R¹⁰ are as defined in formula (I), or a salt thereof as defined in (a) above; or (b) when at least one of R⁴ and R⁵ represents a hydrogen atom, reacting a compound of general formula

 or a salt thereof, wherein R¹, R², R³, Q, m, n, X¹, X², X³, X⁴ and T are as defined in formula (I), with a compound of general formula (X), R⁶—C(O)—R²⁰, wherein R²⁰ represents a hydrogen atom or a C₁-C₄ alkyl group and R⁶ is as defined in formula (I), in the presence of a reducing agent; or (c) reacting a compound of formula (IX) as defined in (b) above, with a compound of general formula

 wherein L² represents a leaving group (e.g. a halogen atom) and Z and R⁶ are as defined in formula (I); and optionally after (a), (b), or (c) forming a pharmaceutically acceptable salt or solvate of the compound of formula (I) obtained.
 4. A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as in claim 1 in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
 5. A process for the preparation of a pharmaceutical composition as claimed in claim 4 which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as in claim 1 with a pharmaceutically acceptable adjuvant, diluent or carrier.
 6. A method of treating asthma in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, or solvate thereof, or a solvate of a salt thereof,

wherein Z is CR⁴R⁵, wherein R⁴ and R⁵ are CH₂; R¹ represents a 3- to 14-membered saturated or unsaturated ring system which comprises up to two ring carbon atoms that form carbonyl groups and which further comprises up to 4 ring heteroatoms independently selected from nitrogen, oxygen and sulphur, wherein the ring system is optionally substituted by one or more substituents independently selected from: halogen, cyano, nitro, oxo, hydroxyl, C₁-C₈ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁₋₆ alkoxy(C₂-C₆ alkyl), C₃-C₇ cycloalkyl(C₁-C₆ alkyl), C₁-C₆ alkylthio(C₁-C₆ alkyl), C₁-C₆ alkylcarbonyloxy(C₁-C₆ alkyl), C₁-C₆ alkylS(O)₂(C₁-C₆ alkyl), aryl(C₁-C₆ alkyl), heterocyclyl(C₁-C₆ alkyl), arylS(O)₂(C₁-C₆ alkyl), heterocyclylS(O)₂(C₁-C₆ alkyl), aryl(C₁-C₆ alkyl)S(O)₂, heterocyclyl(C₁-C₆ alkyl)S(O)₂, C₂-C₆ alkenyl, C₁-C₆ alkoxy, carboxy-substituted C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ hydroxyalkoxy, C₁-C₆ alkylcarboxy-substituted C₁-C₆ alkoxy, aryloxy, heterocyclyloxy, C₁-C₆ alkylthio, C₃-C₇ cycloalkyl(C₁-C₆ alkylthio), C₃-C₆ alkynylthio, C₁-C₆ alkylcarbonylamino, C₁-C₆ haloalkylcarbonylamino, SO₃H, —NR⁷R⁸, —C(O)NR²³R²⁴, S(O)₂NR¹⁸R¹⁹, S(O)₂R²⁰, R²⁵C(O), carboxyl, C₁-C₆ alkoxycrbonyl, aryl and heterocyclyl; wherein the foregoing aryl and heterocyclyl moieties are optionally substituted by one or more of halogen, oxo, hydroxy, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl(C₁-C₆ alkyl), C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, S(O)₂(C₁-C₆ alkyl), C(O)NH₂, carboxy or C₁-C₆ alkoxycarbonyl; m is 0; n is 2; each R² and R³ independently represents a hydrogen atom or a C₁-C₄ alkyl group, or (CR²R³)_(n) represents C₃-C₇ cycloalkyl optionally substituted by C₁-C₄ alkyl; T represents a group C(O)NR¹⁰; X¹, X², X³ and X⁴ are, independently, CH₂; R⁴ and R⁵ each independently represent a hydrogen atom or a C₁-C₄ alkyl group; R⁶ is phenyl optionally substituted by one or more of: halogen, cyano, nitro, oxo, hydroxyl, C₁-C₈ alkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ haloalkyl, C₁₋₆ alkoxy(C₁-C₆ alkyl), C₃-C₇ cycloalkyl(C₁-C₆ alkyl), C₁-C₆ alkylthio(C₃-C₆ alkyl), C₁-C₆ alkylcarbonyloxy(C₁-C₆ alkyl), C₁-C₆ alkylS(O)₂(C₁-C₆ alkyl), aryl(C₁-C₆ alkyl), heterocyclyl(C₁-C₆ alkyl), arylS(O)₂(C₁-C₆ alkyl), heterocyclylS(O)₂(C₁-C₆ alkyl), aryl(C₁-C₆ alkyl)S(O)₂, heterocyclyl(C₁-C₆ alkyl)S(O)₂, C₂-C₆ alkenyl, C₁-C₆ alkoxy, carboxy-substituted C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, C₁-C₆ hydroxyalkoxy, C₁-C₆ alkylcarboxy-substituted C₁-C₆ alkoxy, aryloxy, heterocyclyloxy, C₁-C₆ alkylthio, C₃-C₇ cycloalkyl(C₁-C₆ alkylthio), C₃-C₆ alkynylthio, C₁-C₆ alkylcarbonylamino, C₁-C₆ haloalkylcarbonylamino, SO₃H, —NR¹⁶R¹⁷, —C(O)NR²¹R²², S(O)₂NR¹³R¹⁴, S(O)₂R¹⁵, R²⁶C(O), carboxyl, C₁-C₆ alkoxycarbonyl, aryl and heterocyclyl; wherein the foregoing aryl and heterocyclyl moieties are optionally substituted by one or more of halogen, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl(C₁-C₆ alkyl), C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, S(O)₂(C₁-C₆ alkyl), C(O)NH₂, carboxy or C₁-C₆ alkoxycarbonyl; R⁷, R⁸, R⁹, R¹⁰, R¹³, R¹⁴, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²¹, R²², R²³ and R²⁴ are, independently hydrogen, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₃-C₇ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl) or phenyl(C₁-C₆ alkyl); and, R¹⁵ R²⁰ are, independently, C₁-C₆ alkyl, C₁-C₆ hydroxyalkyl, C₃-C₆ cycloalkyl, C₃-C₇ cycloalkyl(C₁-C₄ alkyl) or C₁-C₆ alkyl optionally substituted by phenyl; R²⁵ and R²⁶ are, independently, C₁-C₆ alkyl or phenyl (optionally substituted by one or more of halogen, nitro, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, phenyl(C₁-C₆ alkyl), C₁-C₆ alkoxy, C₁-C₆ haloalkoxy, S(O)₂(C₁-C₆ alkyl), C(O)NH₂, carboxy or C₁-C₆ alkoxycarbonyl). 